Therapeutic compounds, formulations, and uses thereof

ABSTRACT

Provided herein are compositions, formulations, and (e.g., oral) dosage forms comprising a compound of Formula (I). In specific instances, such compositions comprise an emulsifier, a solubilizer, a polyethylene glycol, a surfactant, and an antioxidant. In some instances, such compositions are useful for the treatment of fibrosis, cancer, and/or chronic inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2021/014642, filed on Jan. 22, 2021, which claims the benefit andpriority of U.S. Provisional Application No. 62/965,738, filed on Jan.24, 2020, the contents of each are hereby incorporated by reference intheir entireties.

TECHNICAL FIELD

Provided herein is a compound of Formula (I), and pharmaceuticalcompositions and uses thereof, such as in the treatment of cancer,fibrosis, or chronic inflammation.

BACKGROUND

While great strides have been made in the treatment of cancer, a cureremains elusive. In recent years, advancements in formulation chemistryhave increased the range of therapeutic compounds that can be utilizedin cancer treatment.

SUMMARY

Provided in some embodiments herein is a compound of Formula (I):

such as for use in therapies for cancer, fibrosis, or chronicinflammation. Provided in certain embodiments are pharmaceuticalcompositions comprising a compound of Formula (I). In general instances,compounds of Formula (I) have low solubility and are very difficult toformulate in a practical and usable form. For example, in someinstances, formulations, such as comprising a combination of Labrasol®and PEG400 (60:40), require unmanageable pill burden at even modestdosing. In certain instances, provided herein are compositions andformulations capable of providing good solubility of a compound ofFormula (I) and/or reducing pill burden in therapies involving acompound of Formula (I).

While a compound of Formula (I) is generally considered to be highlyinsoluble (akin to “brick dust”), in certain instances, compositions andformulations provided herein are able to provide high loading of acompound of Formula (I), good ability to solubilize a compound ofFormula (I), good ability to provide for high bioavailability of acompound of Formula (I), good stability (e.g., chemical and/or physicalstability), and/or reduce pill burden for individuals receivingtherapies involving the administration of a compound of Formula (I).

In some embodiments, a composition, formulation or oral dosage formprovided herein comprises, in addition to the compound of Formula (I),any suitable excipient or combination of excipients. In certainembodiments, the formulation (e.g., excipient or combination ofexcipients thereof) is suitable for providing good solubility of acompound of Formula (I), good physical stability (e.g., good solubilityand/or dispersion of a compound of Formula (I)), good chemical stabilityof a compound of Formula (I), good (e.g., oral) bioavailability of acompound of Formula (I), and/or desirable or therapeutic effect, with amanageable (e.g., fewer than 25 pills per day, or other amount describedherein) or reduced pill burden (e.g., relative to two-componentexcipient systems described herein) and/or an acceptable toxicityprofile (e.g., gastrointestinal toxicity profile, such as due at leastin part to the low or reduced levels of excipient(s) present in thecompositions and formulations provided herein relative to alternativeformulations).

Provided in certain embodiments herein are pharmaceutical compositions,formulations, and oral dosage forms comprising an (e.g., therapeuticallyeffective) amount of a compound of Formula (I):

In some embodiments, provided herein, are methods of using a compound ofFormula (I), or a composition, formulation, or oral dosage formcomprising a compound of Formula (I). In certain embodiments, suchmethods are methods for providing a therapeutic effect, such as treatinga disease or disorder mediated by STAT3, cancer, fibrosis, or chronicinflammation (e.g., with a manageable or reduced pill burden). In someembodiments, methods provided herein comprise administering a compoundof Formula (I), or a composition, formulation, or oral dosage formthereof, such as to achieve a certain pharmacokinetic profile, such asdescribed herein.

Provided herein, in one aspect, is a pharmaceutical compositioncomprising:

-   -   a. a therapeutically effective amount of a compound of Formula        (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to the emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5);    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:1 to about 1:5 (e.g., about 1:2 to about        1:4, e.g., about 1:3);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:2 to about 1:6        (e.g., about 1:3 to about 1:5, e.g., about 1:4);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g.,        about 1:1); and    -   f. an (e.g., optional) antioxidant, the antioxidant being        present in the composition in a weight ratio of compound of        Formula (I) to antioxidant of about 10:1 to about 30:1 (e.g.,        about 15:1 to about 25:1, e.g., about 20:1).        -   Provided herein, in one aspect, is a pharmaceutical            composition comprising:    -   a. a therapeutically effective amount of a compound of Formula        (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to the emulsifier of about 1:3 to about 1:7;    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:10 to about 1:20 (e.g., about 1:11 to        about 1:16);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:12 to about 1:20        (e.g., about 1:15 to about 1:17);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5);    -   f. an (e.g., optional) antioxidant, the antioxidant being        present in the composition in a weight ratio of compound of        Formula (I) to antioxidant of about 2:1 to about 20:1 (e.g.,        about 5:1).

In certain embodiments, the composition is or is a part of aself-emulsifying drug dispersion (SEDD). In certain embodiments, thecomposition is a capsule fill formulation. In certain embodiments, thecomposition further comprises a capsule shell.

In certain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 50 mg/g (e.g., at least 60mg/g, at least 70 mg/g, at least 80 mg/g, or at least 90 mg/g) (e.g.,excluding the mass of a capsule shell). In certain embodiments, thecompound of Formula (I) is present in the formulation in a concentrationof at least 60 mg/mL (e.g., at least 70 mg/mL, at least 80 mg/mL, atleast 90 mg/mL, or at least 100 mg/mL) (e.g., excluding the volume of acapsule shell). In certain embodiments, at least 60 wt. % (e.g., atleast 80 wt. %, at least 90 wt. %, or at least 95 wt. %) of the compoundof Formula (I) is soluble (dissolved) in the composition.

In certain embodiments, the emulsifier is a glyceride emulsifier. Incertain embodiments, the emulsifier comprises optionally polyglycolyzedmedium- and/or long-chain mono-, di-, and/or tri-glyceride(s).

In certain embodiments, the solubilizer is a polyoxyl castor oil or avitamin E polyethylene glycol succinate (TPGS).

In certain embodiments, the polyethylene glycol (PEG) has an averagemolecular weight of about 200 to about 1000 (e.g., about 500 to about700, or about 550 to about 650, or about 600).

In certain embodiments, the surfactant is polysorbate (e.g., polysorbate20).

In certain embodiments, the antioxidant is vitamin E. In certainembodiments, the antioxidant is ascorbyl palmitate. In certainembodiments, the antioxidant is butylated hydroxytoluene. In certainembodiments, the antioxidant is triethyl citrate. In certainembodiments, the antioxidant is citric acid.

In certain embodiments, the composition further comprises a co-solvent(e.g., Transcutol®).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising:

-   -   a. at least 40 mg (e.g., at least 50 mg, at least 60 mg, or at        least 75 mg) of a compound of Formula (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5);    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:1 to about 1:5 (e.g., about 1:2 to about        1:4, e.g., about 1:3);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:2 to about 1:6        (e.g., about 1:3 to about 1:5, e.g., about 1:4);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g. about        1:2); and    -   f. an (e.g., optional) antioxidant, the antioxidant being        present in the composition in a weight ratio of compound of        Formula (I) to antioxidant of about 10:1 to about 30:1 (e.g.,        about 15:1 to about 25:1, e.g., about 20:1).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising:

-   -   a. at least 40 mg (e.g., at least 50 mg, at least 60 mg, or at        least 75 mg) of a compound of Formula (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to emulsifier of about 1:3 to about 1:7;    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:10 to about 1:20 (e.g., about 1:11 to        about 1:16);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:12 to about 1:20        (e.g., about 1:15 to about 1:17);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5);    -   f. an (e.g., optional) antioxidant, the antioxidant being        present in the composition in a weight ratio of compound of        Formula (I) to antioxidant of about 2:1 to about 20:1 (e.g.,        about 5:1).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising atleast 40 mg (e.g., at least 50 mg, at least 60 mg, or at least 75 mg) ofa compound of Formula (I):

In certain embodiments, the oral dosage form further comprises acapsule. In certain embodiments, the composition is configured entirelywithin the capsule. In certain embodiments, the capsule is size 00 orsmaller.

In certain embodiments, the pharmaceutical composition further comprisesan emulsifier (e.g., glyceride). In certain embodiments, the emulsifieris present in the composition in a weight ratio of compound of Formula(I) to the emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5). Incertain embodiments, the emulsifier is present in the composition in aweight ratio of compound of Formula (I) to the emulsifier of about 1:3to about 1:7.

In certain embodiments, the pharmaceutical composition further comprisesa solubilizer. In certain embodiments, the solubilizer is present in thecomposition in a weight ratio of compound of Formula (I) to solubilizerof about 1:1 to about 1:5 (e.g., about 1:2 to about 1:4, e.g., about1:3). In certain embodiments, the solubilizer is present in thecomposition in a weight ratio of compound of Formula (I) to solubilizerof about 1:10 to about 1:20 (e.g., about 1:11 to about 1:16).

In certain embodiments, the pharmaceutical composition further comprisesa polyethylene glycol (PEG). In certain embodiments, the polyethyleneglycol is present in the composition in a weight ratio of compound ofFormula (I) to polyethylene glycol of about 1:2 to about 1:6 (e.g.,about 1:3 to about 1:5, e.g., about 1:4). In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:12 to about1:20 (e.g., about 1:15 to about 1:17).

In certain embodiments, the pharmaceutical composition further comprisesa surfactant. In certain embodiments, the surfactant is present in thecomposition in a weight ratio of compound of Formula (I) to surfactantof about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g. about1:2). In certain embodiments, the surfactant is present in thecomposition in a weight ratio of compound of Formula (I) to surfactantof about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5).

In certain embodiments, the pharmaceutical composition further comprisesan antioxidant. In certain embodiments, the antioxidant is present inthe composition in a weight ratio of compound of Formula (I) toantioxidant of about 10:1 to about 30:1 (e.g., about 15:1 to about 25:1,e.g., about 20:1). In certain embodiments, the antioxidant is present inthe composition in a weight ratio of compound of Formula (I) toantioxidant of about 2:1 to about 20:1 (e.g., about 5:1).

In certain embodiments, the composition is as described in any of thepreviously described embodiments.

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a high dose of acompound of Formula (I):

the high dose of the compound of Formula (I) comprising administrationof at least 15 mg/kg/day of the compound of Formula (I) to theindividual.

In certain embodiments, administering the compound of Formula (I)comprises administering any pharmaceutical composition, formulation, ororal dosage form described herein. In certain embodiments, the methodcomprises administering the compound of Formula (I) in any suitabledose. In certain embodiments, the method comprises administering thecompound of Formula (I) in any suitable number of oral dosage forms perday. In certain embodiments, the method comprises administering thecompound of Formula (I) in a total of no more than 50 oral dosage formsper day. In certain embodiments, the method comprises administering thecompound of Formula (I) in a total of no more than 25 oral dosage formsper day. In certain embodiments, the method comprises administering thecompound of Formula (I) in a total of no more than 15 oral dosage formsper day.

In certain embodiments, the method comprises administering the compoundof Formula (I) in a total of no more than 0.3 oral dosage forms per 1 kgof mass of the individual per day. In certain embodiments, the methodcomprises administering the compound of Formula (I) in a total of nomore than 0.35 oral dosage forms per 1 kg of mass of the individual perday. For example, in an individual weighing 75 kg, the number of oraldosage forms administered per day would not exceed about 26 (i.e., 0.35oral dosage forms per 1 kg of mass*75 kg of mass=26.25 oral dosageforms).

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a plurality of oraldosage forms, the plurality of oral dosage forms collectively comprisinga therapeutically effective amount of a compound of Formula (I):

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a plurality of oraldosage forms, the plurality of oral dosage forms collectively comprisinga therapeutically effective amount of a compound of Formula (I):

the plurality of oral dosage forms comprising no more than 0.35 oraldosage forms for every 1 kg of mass of the individual per day (e.g., onaverage or maximum).

In some embodiments, any suitable (e.g., therapeutically effective)amount of a compound of Formula (I) is provided to an individual, suchas an individual in need thereof. In certain embodiments, the amount ofcompound of Formula (I) varies depending on the disease treated. Forexample, in some instances, higher doses are utilized in cancertherapies relative to fibrosis or chronic inflammation diseases. In someembodiments, the method comprises administering at least 1 mg/kg/day ofthe compound of Formula (I) to the individual. In specific embodiments,the method comprises administering at least 2 mg/kg/day of the compoundof Formula (I) to the individual. In more specific embodiments, themethod comprises administering at least 5 mg/kg/day of the compound ofFormula (I) to the individual. In certain embodiments, the methodcomprises administering at least 10 mg/kg/day of the compound of Formula(I) to the individual. In certain embodiments, the method comprisesadministering at least 15 mg/kg/day of the compound of Formula (I) tothe individual. In certain embodiments, the method comprisesadministering at least 20 mg/kg/day of the compound of Formula (I) tothe individual. In certain embodiments, the method comprisesadministering at least 25 mg/kg/day of the compound of Formula (I) tothe individual. In certain embodiments, the method comprisesadministering at least 30 mg/kg/day of the compound of Formula (I) tothe individual.

In certain embodiments, a cancer treated according to a method providedherein is a liver cancer, lung cancer, head and neck cancer, breastcancer, skin cancer, kidney cancer, testicular cancer, colon cancer,rectal cancer, gastric cancer, metastatic melanoma, prostate cancer,ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, analcancer, prostate cancer, multiple myeloma, post-transplantlymphoproliferative disease, restenosis, myelodysplastic syndrome,leukemia, lymphoma, or acute myelogenous leukemia. In some embodiments,a cancer treated according to a method provided herein is a livercancer, lung cancer, hepatocellular carcinoma, head and neck squamouscell carcinoma, non-small cell lung cancer, or estrogenreceptor-positive breast cancer. In some embodiments, a cancer treatedaccording to a method provided herein is head and neck cancer, lungcancer, liver cancer, breast cancer, ovarian cancer, colon cancer,multiple myeloma, leukemia, or pancreatic cancer. In some embodiments,the leukemia is acute myelogenous leukemia.

In some embodiments, chronic inflammation treated herein is inflammatorybowel disease (IBD), ulcerative colitis, Crohn's disease, asthma,anaphylaxis, cancer cachexia, chronic kidney disease cachexia,nonalcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis,multiple sclerosis, or pancreatitis. In some embodiments, chronicinflammation treated herein is inflammatory bowel disease (IBD),ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancercachexia, chronic kidney disease cachexia, or nonalcoholicsteatohepatitis (NASH). In some embodiments, the anaphylaxis comprisesanaphylactic shock.

In certain embodiments, the fibrosis is skin fibrosis (or dermalfibrosis), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrowfibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liverfibrosis, retroperitoneum, renal fibrosis, myelofibrosis, non-alcoholicfatty liver disease, steatohepatitis, systemic sclerosis (includingdiffuse systemic sclerosis or limited systemic sclerosis),endomyocardial fibrosis, myocardial infarction, atrial fibrosis,mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemicfibrosis, Keloid, arthrofibrosis, adhesive capsulitis, or cysticfibrosis. In certain embodiments, the fibrosis is skin fibrosis(scleroderma), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bonemarrow fibrosis, intestine fibrosis, pancreatic fibrosis, jointfibrosis, liver fibrosis, retroperitoneum, myelofibrosis, non-alcoholicfatty liver disease, steatohepatitis, or systemic sclerosis. In certainembodiments, the fibrosis is skin fibrosis (scleroderma), cardiacfibrosis, cirrhosis, or pulmonary fibrosis.

In certain embodiments, the fibrosis is fibrosis following exposure tocertain drugs such as chemotherapy, fibrosis following exposure toenvironmental or other toxins or allergens, fibrosis occurring after anischemia/reperfusion injury such as myocardial infarction orhypotension, fibrosis occurring after radiation, fibrosis followinghepatitis induced by alcohol, toxins, drugs or infections, primarybiliary cirrhosis, fibrosis following viral infections involving theheart, liver, or lung, and/or idiopathic retroperitoneal fibrosis.

In certain embodiments, any method provided herein is a method oftreating muscle wasting, muscle weakness, or cachexia. The muscleweakness and/or muscle wasting and/or cachexia may have an unknown causeor it may be associated with an underlying condition. The underlyingcondition may be a catabolic condition. In some embodiments, theunderlying medical condition associated with cachexia is least renalfailure, cancer, AIDS, HIV infection, chronic obstructive lung disease(including emphysema), multiple sclerosis, congestive heart failure,tuberculosis, familial amyloid polyneuropathy, acrodynia, hormonaldeficiency, metabolic acidosis, infectious disease, chronicpancreatitis, autoimmune disorder, celiac disease, Crohn's disease,electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever,long bone fracture, hyperthyroidism, prolonged steroid therapy, surgery,bone marrow transplant, atypical pneumonia, brucellosis, endocarditis,Hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome,polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus,myositis, polymyositis, dematomyosytis, rheumatological diseases,autoimmune disease, collagen-vascular disease, visceral leishmaniasis,prolonged bed rest, and/or addiction to drugs, such as amphetamine,opiates, or barbitutates.

In certain embodiments, any method provided herein is a method oftreating, preventing, or reducing the risk or severity of an allergicreaction. In some embodiments, the allergic reaction is inducedfollowing an exposure to an allergen. In some embodiments, the allergenis a food allergen (such as milk, legumes, shellfish, tree nuts, eggs,fish, soy, and wheat), an environmental allergen or seasonal allergen(such as pollen or mold), a venom allergen (such as from wasp, bee, ant,hornet, yellow jacket, or asp), a medication allergen (such asanesthetics, β-lactam antibiotics, aspirin, non-steroidalanti-inflammatory drug, chemotherapy, vaccine, protamine, or herbalpreparations), or latex. In some embodiments, the allergic reaction isanaphylaxis, anaphylactic shock, allergic rhinitis, urticaria, foodallergy, drug allergy, hymenoptera allerga, bronchial constriction,asthma, or eczema.

In certain embodiments, any method provided herein is a method oftreating a viral infection. In some embodiments, the viral infection isa chronic viral infection. In some embodiments, the chronic viralinfection is AIDS, HIV infection, Hepatitis B infection, Hepatitis Cvirus infection, or Epstein-Barr virus infection.

In certain embodiments, any method provided herein is a method oftreating graft-versus-host diseases, pulmonary lymphangioleiomyomatosis,chagasic cardiomyopathy, age-related macular degeneration, amyloidosis,astrogliosis in Alzheimer's or other neurodegenerative diseases, orfamilial amyloid polyneuropathy.

In certain embodiments, any method provided herein is a method oftreating a neurodegenerative disease. In some embodiments, theneurodegenerative disease is chemotherapy-induced peripheral neuropathy,diabetic neuropathy, or chemobrain.

In certain embodiments, any method provided herein is a method oftreating or reducing the risk or severity of insulin resistance. In someembodiments, the insulin resistance is a result of an underlyingcondition. In some embodiments, the insulin resistance is associatedwith muscle of the individual being treated. In some embodiments, theinsulin resistance is caused by any reason for the individual, such aselevated free fatty acids in the blood, obesity, being overweight,having visceral fat, having a high fructose intake, having inflammation,being inactive, dysbiosis of the gut microbiota, and/or beinggenetically predisposed. In certain embodiments, any method providedherein is a method of treating or reducing the risk or severity ofmedical conditions associated with insulin resistance or that arecomplications of insulin resistance at least in part, such as severehigh blood sugar; severe low blood sugar; heart attack; stroke; kidneydisease (including chronic, for example, chronic kidney disease (CKD));eye problems; cancer; non-alcoholic fatty liver disease (NAFLD);polycystic ovarian syndrome (PCOS); metabolic syndrome; diabetes; orAlzheimer's disease, for example. In certain embodiments, the insulinresistance is a hallmark of metabolic syndrome and type 2 diabetes.Metabolic syndrome is a group of risk factors associated with type 2diabetes and heart disease. Its symptoms include high bloodtriglycerides, blood pressure, belly fat, and blood sugar, as well aslow HDL (good) cholesterol levels.

In specific embodiments, any method provided herein is a method oftreating cancer, such as a cancer described herein. In some otherspecific embodiments, any method provided herein is a method fortreating fibrosis, such as a type of fibrosis or disease or disorderassociated therewith described herein. In some other specificembodiments, any method provided herein is a method for treating chronicinflammation, such as any type of chronic inflammation described herein.In certain alternative embodiments, any therapeutic method providedherein is a method of treating a STAT3-mediated disorder, such as byadministering a compound of Formula (I) using any administrative methodor formulation described herein.

Provided herein, in another aspect, is a method of providing to anindividual an improved C_(max) or AUC_(0-∞) of a compound of Formula(I):

the improved C_(max) or AUC_(0-∞) being at least 1.1 times (e.g., atleast 1.2 times, at least 1.3 times, or more) greater than the effectobtained by administering an otherwise identical amount of a compound ofFormula (I) in a formulation of PEG400 and Labrasol® (40:60 by weight).

In certain embodiments, the method has an administration protocol of anyof the previously described embodiments. In certain embodiments, thecompound of Formula (I) is administered in a pharmaceutical compositionor in one or more oral dosage forms of any of the previously describedembodiments.

Provided herein, in another aspect, is a crystalline form of a compoundof Formula (I):

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern comprising peaks at 8.13±0.2°,16.50±0.2°, 18.41±0.2°, 21.77±0.2°, and 22.64±0.2° two theta. In certainembodiments, the X-ray powder diffraction pattern further comprises atleast one peak selected from 9.56±0.2°, 11.43±0.2°, 12.75±0.2°, and14.66±0.2° two theta. In certain embodiments, the X-ray powderdiffraction pattern further comprises at least one peak selected from19.70±0.2°, 20.21±0.2°, 20.81±0.2°, and 24.43±0.2° two theta. In certainembodiments, the X-ray powder diffraction pattern further comprises atleast one peak selected from 26.10±0.2°, 29.29±0.2°, and 30.75±0.2° twotheta. In certain embodiments, the crystalline form is characterized byan X-ray powder diffraction pattern comprising peaks at 8.13±0.2°,9.56±0.2°, 11.43±0.2°, 12.75±0.2°, 14.66±0.2°, 16.50±0.2°, 18.41±0.2°,from 19.70±0.2°, 20.21±0.2°, 20.81±0.2°, 21.77±0.2°, 22.64±0.2°,24.43±0.2°, 26.10±0.2°, 29.29±0.2°, and 30.75±0.2° two theta.

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern substantially as set forth in FIG. 1.

In certain embodiments, any method provided herein comprisesadministering a compound of Formula (I) having a crystalline formdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of thecrystalline form of the compound of Formula (I).

FIG. 2 shows the one-stage dissolution profiles of various formulationsof a compound of Formula (I).

FIG. 3 shows the two-stage dissolution profiles of various formulationsof a compound of Formula (I).

FIG. 4 shows the design of the rat pharmacokinetics study of variousformulations of a compound of Formula (I).

FIG. 5 shows the individual human pharmacokinetic parameters by cohortfor the 12-hour time course of a single dose of the two-componentformulation system.

FIG. 6 shows the mean human pharmacokinetic parameters by cohort for the12-hour time course of a single dose of the two-component formulationsystem.

FIG. 7 shows the results of pharmacokinetics analyses for variousformulations of compounds of Formula (I).

FIG. 8 shows the mean area under the curve per dose body weight forvarious formulations of a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The term “oral dosage form” as used herein and unless otherwiseindicated, refers to a pharmaceutical composition that has beenformulated or otherwise prepared for oral administration, such as in adiscrete form.

Provided in certain embodiments herein are compositions, formulations,and oral dosage forms comprising a compound of Formula (I):

In some embodiments, the compositions, formulations, and oral dosageforms described herein comprise a compound of Formula (I) as apharmaceutically acceptable salt, a hydrate, or a solvate.

Also provided herein are methods of using a compound of Formula (I),such as in therapeutic or other methods described herein. In someembodiments, the methods involve the use of (e.g., comprise theadministration of) a compound of Formula (I), wherein the compound ofFormula (I) is formulated in a manner described herein (e.g., is presentin a composition as described herein). In some embodiments, a compoundof Formula (I) (e.g., as formulated herein) is utilized in a method fortreating a disease or disorder mediated by STAT3, or a disease ordisorder that is otherwise treatable with a STAT3 inhibitor. In specificembodiments, provided herein are methods of treating cancer. In otherspecific embodiments, provided herein are methods of treating fibrosis.In still other specific embodiments, provided herein are methods oftreating chronic inflammation.

While a compound of Formula (I) is generally considered to be highlyinsoluble (“brick dust”), in certain instances, such compositionsprovided are able to provide high loading of a compound of Formula (I),good ability to solubilize a compound of Formula (I), good ability toprovide for high bioavailability of a compound of Formula (I), goodstability (e.g., chemical and/or physical stability), and/or reduce pillburden for individuals receiving therapies involving the administrationof a compound of Formula (I). Also provided in various embodimentsherein are methods, such as therapeutic methods for cancer, fibrosis,and/or chronic inflammation, involving the administration of a compoundof Formula (I) or compositions or formulations provided herein.

In some embodiments, a composition, formulation or oral dosage formprovided herein comprises, in addition to the compound of Formula (I),any suitable excipient or combination of excipients. In certainembodiments, the excipient or combination of excipients is suitable forproviding good solubility of a compound of Formula (I), good physicalstability (e.g., good solubility and/or dispersion of a compound ofFormula (I)), good chemical stability of a compound of Formula (I), good(e.g., oral) bioavailability of a compound of Formula (I), and/ordesirable or therapeutic effect, with a manageable (e.g., fewer than 25pills per day, or other amount described herein) or reduced pill burden(e.g., relative to two component excipient systems described herein).

In some embodiments, provided herein is a (e.g., pharmaceutical)composition comprising a compound of Formula (I) and an emulsifier, asolubilizer, a solvent, a surfactant, and/or an antioxidant. In specificembodiments, the composition comprises a solvent and a solubilizer. Inmore specific embodiments, the composition comprises an emulsifier, asolubilizer, and a solvent. In still more specific embodiments, thecomposition comprises an emulsifier, a solubilizer, a surfactant, and asolvent. In yet more specific embodiments, the composition comprises anemulsifier, a solubilizer, a surfactant, an antioxidant, and a solvent.In certain embodiments, the composition or formulation is aself-emulsifying drug dispersion (SEDD).

In certain embodiments, the composition, dosage form, or formulationdescribed herein has a pill burden at least 2-fold lower than (i.e., ½)that of the 60:40 Labrasol®/PEG400 formulation. In certain embodiments,the composition, dosage form, or formulation described herein has a pillburden at least 2.1-fold lower than that of the 60:40 Labrasol®/PEG400formulation. In certain embodiments, the formulation described hereinhas a pill burden at least 2.2-fold lower than that of the 60:40Labrasol®/PEG400 formulation. In certain embodiments, the composition,dosage form, or formulation described herein has a pill burden at least2.3-fold lower than that of the 60:40 Labrasol®/PEG400 formulation. Incertain embodiments, the composition, dosage form, or formulationdescribed herein has a pill burden at least 2.4-fold lower than that ofthe 60:40 Labrasol®/PEG400 formulation. In certain embodiments, thecomposition, dosage form, or formulation described herein has a pillburden at least 2.5-fold lower than that of the 60:40 Labrasol®/PEG400formulation. In certain embodiments, the composition, dosage form, orformulation described herein has a pill burden at least 2.6-fold lowerthan that of the 60:40 Labrasol®/PEG400 formulation. In certainembodiments, the composition, dosage form, or formulation describedherein has a pill burden at least 2.7-fold lower than that of the 60:40Labrasol®/PEG400 formulation.

In certain embodiments, the composition, dosage form, or formulationdescribed herein displays a droplet size of no more than 200 nm whendispersed in (e.g., simulated) gastric/intestinal fluids. In certainembodiments, the composition, dosage form, or formulation describedherein displays a droplet size of no more than 175 nm when dispersed in(e.g., simulated) gastric/intestinal fluids. In certain embodiments, thecomposition, dosage form, or formulation described herein displays adroplet size of no more than 150 nm when dispersed in (e.g., simulated)gastric/intestinal fluids. In certain embodiments, the composition,dosage form, or formulation described herein displays a droplet size ofno more than 125 nm when dispersed in (e.g., simulated)gastric/intestinal fluids.

In certain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.5when dispersed in (e.g., simulated) gastric/intestinal fluids. Incertain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.45when dispersed in (e.g., simulated) gastric/intestinal fluids. Incertain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.4when dispersed in (e.g., simulated) gastric/intestinal fluids. Incertain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.35when dispersed in (e.g., simulated) gastric/intestinal fluids. Incertain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.3when dispersed in (e.g., simulated) gastric/intestinal fluids. Incertain embodiments, the composition, dosage form, or formulationdescribed herein displays a polydispersity index of no more than 0.25when dispersed in (e.g., simulated) gastric/intestinal fluids.

In certain embodiments, the composition, dosage form, or formulationdescribed herein possesses a compound of Formula (I) purity of at least85% after 5 months (e.g., at room temperature and 60% RH). In certainembodiments, the composition, dosage form, or formulation describedherein possesses a compound of Formula (I) purity of at least 90% after5 months (e.g., at room temperature and 60% RH). In certain embodiments,the composition, dosage form, or formulation described herein possessesa compound of Formula (I) purity of at least 95% after 5 months (e.g.,at room temperature and 60% RH). In certain embodiments, thecomposition, dosage form, or formulation described herein possesses acompound of Formula (I) purity of at least 96% after 5 months (e.g., atroom temperature and 60% RH). In certain embodiments, the composition,dosage form, or formulation described herein possesses a compound ofFormula (I) purity of at least 97% after 5 months (e.g., at roomtemperature and 60% RH). In certain embodiments, the composition, dosageform, or formulation described herein possesses a compound of Formula(I) purity of at least 98% after 5 months (e.g., at room temperature and60% RH).

In certain embodiments, the composition, dosage form, or formulationdescribed herein possesses a greater (e.g., at least 1.05 times, atleast 1.1 times, at least 1.15 times, at least 1.2 times, at least 1.25times, at least 1.3 times, or more) C_(max) than an otherwise similarlyprovided 60:40 Labrasol®/PEG400 formulation of a compound of Formula(I). In certain embodiments, the composition, dosage form, orformulation described herein possesses a comparable (e.g., about80-120%, about 90-110%, or the like) total systemic exposure(AUC_(last)) and dose-normalized AUC (AUC_(∞)_D_obs) to an otherwisesimilarly provided 60:40 Labrasol®/PEG400 formulation of a compound ofFormula (I).

Provided herein, in one aspect, is a pharmaceutical compositioncomprising:

-   -   a. a therapeutically effective amount of a compound of Formula        (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to the emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5);    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:1 to about 1:5 (e.g., about 1:2 to about        1:4, e.g., about 1:3);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:2 to about 1:6        (e.g., about 1:3 to about 1:5, e.g., about 1:4);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g. about        1:2); and    -   f. an antioxidant, the antioxidant being present in the        composition in a weight ratio of compound of Formula (I) to        antioxidant of about 10:1 to about 30:1 (e.g., about 15:1 to        about 25:1, e.g., about 20:1).

Provided herein, in one aspect, is a pharmaceutical compositioncomprising:

-   -   a. a therapeutically effective amount of a compound of Formula        (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to the emulsifier of about 1:3 to about 1:7;    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:10 to about 1:20 (e.g., about 1:11 to        about 1:16);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:12 to about 1:20        (e.g., about 1:15 to about 1:17);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5);    -   f. an antioxidant, the antioxidant being present in the        composition in a weight ratio of compound of Formula (I) to        antioxidant of about 2:1 to about 20:1 (e.g., about 5:1).

In certain embodiments, the emulsifier is present in the composition ina weight ratio of compound of Formula (I) to the emulsifier of about1:1. In certain embodiments, the emulsifier is present in thecomposition in a weight ratio of compound of Formula (I) to theemulsifier of about 1:2. In certain embodiments, the emulsifier ispresent in the composition in a weight ratio of compound of Formula (I)to the emulsifier of about 1:3. In certain embodiments, the emulsifieris present in the composition in a weight ratio of compound of Formula(I) to the emulsifier of about 1:4. In certain embodiments, theemulsifier is present in the composition in a weight ratio of compoundof Formula (I) to the emulsifier of about 1:5. In certain embodiments,the emulsifier is present in the composition in a weight ratio ofcompound of Formula (I) to the emulsifier of about 1:6. In certainembodiments, the emulsifier is present in the composition in a weightratio of compound of Formula (I) to the emulsifier of about 1:7. Incertain embodiments, the emulsifier is present in the composition in aweight ratio of compound of Formula (I) to the emulsifier of about1:1.5.

In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:1.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:2.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:3.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:4.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:5.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:4.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:6.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:4.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:7.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:4.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:8.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:4.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:9.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:10.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:11.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:12.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:13.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:14.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:15.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:16.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:17.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:18.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:19.In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:20.

In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:1. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:2. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:3. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:4. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:5. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:6. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:7. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:8. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:9. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:10. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:11. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:12. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:13. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:14. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:15. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:16. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:17. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:18. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:19. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:20.

In certain embodiments, the surfactant is present in the composition ina weight ratio of compound of Formula (I) to surfactant of about 4:1. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 3:1. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 2:1. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:1. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:2. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:3. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:4. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:5. Incertain embodiments, the surfactant is present in the composition in aweight ratio of compound of Formula (I) to surfactant of about 1:6.

In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 2:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 3:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 4:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 5:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 6:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 7:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 8:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 9:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 10:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 11:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 12:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 13:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 14:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 15:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 16:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 17:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 18:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 19:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 20:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 21:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 22:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 23:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 24:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 25:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 26:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 27:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 28:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 29:1.In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 30:1.

In certain embodiments, the composition is or is a part of aself-emulsifying drug dispersion (SEDD). In certain embodiments, thecomposition is a capsule fill formulation. In certain embodiments, thecomposition further comprises a capsule shell.

In certain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 50 mg/g (e.g., at least 60mg/g, at least 70 mg/g, at least 80 mg/g, or at least 90 mg/g) (e.g.,excluding the mass of a capsule shell). In certain embodiments, thecompound of Formula (I) is present in the formulation in a concentrationof at least 50 mg/g. In certain embodiments, the compound of Formula (I)is present in the formulation in a concentration of at least 60 mg/g. Incertain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 70 mg/g. In certainembodiments, the compound of Formula (I) is present in the formulationin a concentration of at least 80 mg/g. In certain embodiments, thecompound of Formula (I) is present in the formulation in a concentrationof at least 90 mg/g.

In certain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 60 mg/mL (e.g., at least 70mg/mL, at least 80 mg/mL, at least 90 mg/mL, or at least 100 mg/mL)(e.g., excluding the volume of a capsule shell). In certain embodiments,the compound of Formula (I) is present in the formulation in aconcentration of at least 60 mg/mL. In certain embodiments, the compoundof Formula (I) is present in the formulation in a concentration of atleast 70 mg/mL. In certain embodiments, the compound of Formula (I) ispresent in the formulation in a concentration of at least 80 mg/mL. Incertain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 90 mg/mL. In certainembodiments, the compound of Formula (I) is present in the formulationin a concentration of at least 100 mg/mL.

In certain embodiments, at least 60 wt. % (e.g., at least 80 wt. %, atleast 90 wt. %, or at least 95 wt. %) of the compound of Formula (I) issoluble (dissolved) in the composition. In certain embodiments, at least60 wt. % of the compound of Formula (I) is soluble (dissolved) in thecomposition. In certain embodiments, at least 80 wt. % of the compoundof Formula (I) is soluble (dissolved) in the composition. In certainembodiments, at least 90 wt. % of the compound of Formula (I) is soluble(dissolved) in the composition. In certain embodiments, at least 95 wt.% of the compound of Formula (I) is soluble (dissolved) in thecomposition.

In certain embodiments, the emulsifier is a glyceride emulsifier. Incertain embodiments, the emulsifier comprises optionally polyglycolyzedmedium- and/or long-chain mono-, di-, and/or tri-glyceride(s). Incertain embodiments, the emulsifier comprises a medium-chainmono-glyceride. In certain embodiments, the emulsifier comprises apolyglycolyzed medium-chain mono-glyceride. In certain embodiments, theemulsifier comprises a long-chain mono-glyceride. In certainembodiments, the emulsifier comprises a polyglycolyzed long-chainmono-glyceride. In certain embodiments, the emulsifier comprises amedium-chain di-glyceride. In certain embodiments, the emulsifiercomprises a polyglycolyzed medium-chain di-glyceride. In certainembodiments, the emulsifier comprises a long-chain di-glyceride. Incertain embodiments, the emulsifier comprises a polyglycolyzedlong-chain di-glyceride. In certain embodiments, the emulsifiercomprises a medium-chain tri-glyceride. In certain embodiments, theemulsifier comprises a polyglycolyzed medium-chain tri-glyceride. Incertain embodiments, the emulsifier comprises a long-chaintri-glyceride. In certain embodiments, the emulsifier comprises apolyglycolyzed long-chain tri-glyceride.

In certain embodiments, the emulsifier is Labrasol®. In certainembodiments, the emulsifier is Capmul® MCM. In certain embodiments, theemulsifier is Capmul® MCM EP. In certain embodiments, the emulsifier isCapmul® C8 EP. In certain embodiments, the emulsifier is Capryol® 90.

In certain embodiments, the solubilizer is a polyoxyl castor oil or avitamin E polyethylene glycol succinate (TPGS). In certain embodiments,the solubilizer is a polyoxyl castor oil. In certain embodiments, thesolubilizer is a vitamin E polyethylene glycol succinate. In certainembodiments, the surfactant is Kolliphor® RH 40. In certain embodiments,the solubilizer is Vitamin E TPGS.

In certain embodiments, the polyethylene glycol (PEG) has an averagemolecular weight of about 200 to about 1000 (e.g., about 500 to about700, or about 550 to about 650, or about 600). In certain embodiments,the polyethylene glycol (PEG) has an average molecular weight of about200 to 1000. In certain embodiments, the polyethylene glycol (PEG) hasan average molecular weight of about 500 to 700. In certain embodiments,the polyethylene glycol (PEG) has an average molecular weight of about550 to 650. In certain embodiments, the polyethylene glycol (PEG) has anaverage molecular weight of about 600.

In certain embodiments, the polyethylene glycol (PEG) is PEG200. Incertain embodiments, the polyethylene glycol (PEG) is PEG300. In certainembodiments, the polyethylene glycol (PEG) is PEG400. In certainembodiments, the polyethylene glycol (PEG) is PEG500. In certainembodiments, the polyethylene glycol (PEG) is PEG600. In certainembodiments, the polyethylene glycol (PEG) is PEG700. In certainembodiments, the polyethylene glycol (PEG) is PEG800. In certainembodiments, the polyethylene glycol (PEG) is PEG900. In certainembodiments, the polyethylene glycol (PEG) is PEG1000.

In certain embodiments, the surfactant is polysorbate (e.g., polysorbate20). In certain embodiments, the surfactant is polysorbate 20. Incertain embodiments, the surfactant is polysorbate 40. In certainembodiments, the surfactant is polysorbate 60. In certain embodiments,the surfactant is polysorbate 80.

In certain embodiments, the antioxidant is vitamin E. In certainembodiments, the antioxidant is ascorbyl palmitate. In certainembodiments, the antioxidant is butylated hydroxytoluene. In certainembodiments, the antioxidant is triethyl citrate. In certainembodiments, the antioxidant is citric acid.

In certain embodiments, the composition further comprises a co-solvent(e.g., Transcutol®). In certain embodiments, the composition furthercomprises Transcutol® HP.

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising:

-   -   a. at least 40 mg (e.g., at least 50 mg, at least 60 mg, at        least 75 mg) of a compound of Formula (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to emulsifier of about 1:1 to about 1:2 (e.g., about 1:1.5);    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:1 to about 1:5 (e.g., about 1:2 to about        1:4, e.g., about 1:3);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:2 to about 1:6        (e.g., about 1:3 to about 1:5, e.g., about 1:4);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 2:1 to about 1:2 (e.g., about 1:1 to about 1:2, e.g. about        1:2); and    -   f. an antioxidant, the antioxidant being present in the        composition in a weight ratio of compound of Formula (I) to        antioxidant of about 10:1 to about 30:1 (e.g., about 15:1 to        about 25:1, e.g., about 20:1).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising:

-   -   a. at least 40 mg (e.g., at least 50 mg, at least 60 mg, at        least 75 mg) of a compound of Formula (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a weight ratio of compound of Formula (I)        to emulsifier of about 1:3 to about 1:7;    -   c. a solubilizer, the solubilizer being present in the        composition in a weight ratio of compound of Formula (I) to        solubilizer of about 1:10 to about 1:20 (e.g., about 1:11 to        about 1:16);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a weight ratio of compound of        Formula (I) to polyethylene glycol of about 1:12 to about 1:20        (e.g., about 1:15 to about 1:17);    -   e. a surfactant, the surfactant being present in the composition        in a weight ratio of compound of Formula (I) to surfactant of        about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5);    -   f. an antioxidant, the antioxidant being present in the        composition in a weight ratio of compound of Formula (I) to        antioxidant of about 2:1 to about 20:1 (e.g., about 5:1).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising atleast 40 mg (e.g., at least 50 mg, at least 60 mg, or at least 75 mg) ofa compound of Formula (I):

In certain embodiments, the pharmaceutical composition comprises atleast 40 mg of a compound of Formula (I). In certain embodiments, thepharmaceutical composition comprises at least 50 mg of a compound ofFormula (I). In certain embodiments, the pharmaceutical compositioncomprises at least 60 mg of a compound of Formula (I). In certainembodiments, the pharmaceutical composition comprises at least 75 mg ofa compound of Formula (I).

In certain embodiments, the oral dosage form further comprises acapsule. In certain embodiments, the composition is configured entirelywithin the capsule.

In certain embodiments, the capsule is size 00 or smaller. In certainembodiments, the capsule is size 00. In certain embodiments, the capsuleis size 0E. In certain embodiments, the capsule is size 0. In certainembodiments, the capsule is size 1. In certain embodiments, the capsuleis size 2. In certain embodiments, the capsule is size 3. In certainembodiments, the capsule is size 4. In certain embodiments, the capsuleis size 5.

In certain embodiments, the capsule is size 00E or larger. In certainembodiments, the capsule is size 00E. In certain embodiments, thecapsule is size 000.

A size 5 capsule possesses a volume of 0.13 mL. A size 4 capsulepossesses a volume of 0.20 mL. A size 3 capsule possesses a volume of0.27 mL. A size 2 capsule possesses a volume of 0.36 mL. A size 1capsule possesses a volume of 0.48 mL. A size 0 capsule possesses avolume of 0.68 mL. A size 0E capsule possesses a volume of 0.78 mL. Asize 00 capsule possesses a volume of 0.90 mL. A size 00E capsulepossesses a volume of 1.00 mL. A size 000 capsule possesses a volume of1.37 mL.

In certain embodiments, the pharmaceutical composition further comprisesan emulsifier (e.g., glyceride).

In certain embodiments, the emulsifier is present in the composition ina weight ratio of compound of Formula (I) to the emulsifier of about 1:1to about 1:2 (e.g., about 1:1.5). In certain embodiments, the emulsifieris present in the composition in a weight ratio of compound of Formula(I) to the emulsifier of about 1:1. In certain embodiments, theemulsifier is present in the composition in a weight ratio of compoundof Formula (I) to the emulsifier of about 1:1.5. In certain embodiments,the emulsifier is present in the composition in a weight ratio ofcompound of Formula (I) to the emulsifier of about 1:2. In certainembodiments, the emulsifier is present in the composition in a weightratio of compound of Formula (I) to the emulsifier of about 1:3 to about1:7. In certain embodiments, the emulsifier is present in thecomposition in a weight ratio of compound of Formula (I) to theemulsifier of about 1:3. In certain embodiments, the emulsifier ispresent in the composition in a weight ratio of compound of Formula (I)to the emulsifier of about 1:4. In certain embodiments, the emulsifieris present in the composition in a weight ratio of compound of Formula(I) to the emulsifier of about 1:5. In certain embodiments, theemulsifier is present in the composition in a weight ratio of compoundof Formula (I) to the emulsifier of about 1:6. In certain embodiments,the emulsifier is present in the composition in a weight ratio ofcompound of Formula (I) to the emulsifier of about 1:7.

In certain embodiments, the pharmaceutical composition further comprisesa solubilizer.

In certain embodiments, the solubilizer is present in the composition ina weight ratio of compound of Formula (I) to solubilizer of about 1:1 toabout 1:5 (e.g., about 1:2 to about 1:4, e.g., about 1:3). In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:1. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:2. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:3. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:4. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:5. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:4. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:6. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:4. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:7. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:4. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:8. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:4. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:9. In certainembodiments, the solubilizer is present in the composition in a weightratio of compound of Formula (I) to solubilizer of about 1:10 to about1:20 (e.g., about 1:11 to about 1:16). In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:10. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:11. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:12. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:13. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:14. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:15. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:16. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:17. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:18. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:19. In certain embodiments, thesolubilizer is present in the composition in a weight ratio of compoundof Formula (I) to solubilizer of about 1:20.

In certain embodiments, the pharmaceutical composition further comprisesa polyethylene glycol (PEG).

In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:2 to about 1:6 (e.g., about 1:3 to about 1:5, e.g.,about 1:4). In certain embodiments, the polyethylene glycol is presentin the composition in a weight ratio of compound of Formula (I) topolyethylene glycol of about 1:1. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:2. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:3. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:4. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:5. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:6. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:7. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:8. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:9. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:10. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:11. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:12 to about 1:20 (e.g., about 1:15 to about 1:17). Incertain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:12. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:13. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:14. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:15. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:16. In certain embodiments, the polyethylene glycol ispresent in the composition in a weight ratio of compound of Formula (I)to polyethylene glycol of about 1:17. In certain embodiments, thepolyethylene glycol is present in the composition in a weight ratio ofcompound of Formula (I) to polyethylene glycol of about 1:18. In certainembodiments, the polyethylene glycol is present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:19. In certain embodiments, the polyethylene glycol is present in thecomposition in a weight ratio of compound of Formula (I) to polyethyleneglycol of about 1:20.

In certain embodiments, the pharmaceutical composition further comprisesa surfactant.

In certain embodiments, the surfactant is present in the composition ina weight ratio of compound of Formula (I) to surfactant of about 2:1 toabout 1:2 (e.g., about 1:1 to about 1:2, e.g. about 1:2). In certainembodiments, the surfactant is present in the composition in a weightratio of compound of Formula (I) to surfactant of about 4:1. In certainembodiments, the surfactant is present in the composition in a weightratio of compound of Formula (I) to surfactant of about 3:1. In certainembodiments, the surfactant is present in the composition in a weightratio of compound of Formula (I) to surfactant of about 2:1. In certainembodiments, the surfactant is present in the composition in a weightratio of compound of Formula (I) to surfactant of about 1:2. In certainembodiments, the surfactant is present in the composition in a weightratio of compound of Formula (I) to surfactant of about 1:2 to about 1:6(e.g., about 1:3 to about 1:5). In certain embodiments, the surfactantis present in the composition in a weight ratio of compound of Formula(I) to surfactant of about 1:2. In certain embodiments, the surfactantis present in the composition in a weight ratio of compound of Formula(I) to surfactant of about 1:3. In certain embodiments, the surfactantis present in the composition in a weight ratio of compound of Formula(I) to surfactant of about 1:4. In certain embodiments, the surfactantis present in the composition in a weight ratio of compound of Formula(I) to surfactant of about 1:5. In certain embodiments, the surfactantis present in the composition in a weight ratio of compound of Formula(I) to surfactant of about 1:6.

In certain embodiments, the pharmaceutical composition further comprisesan antioxidant.

In certain embodiments, the antioxidant is present in the composition ina weight ratio of compound of Formula (I) to antioxidant of about 10:1to about 30:1 (e.g., about 15:1 to about 25:1, e.g., about 20:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 21:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 22:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 23:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 24:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 25:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 26:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 27:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 28:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 29:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 30:1. Incertain embodiments, the antioxidant is present in the composition in aweight ratio of compound of Formula (I) to antioxidant of about 2:1 toabout 20:1 (e.g., about 5:1). In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 2:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 3:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 4:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 5:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 6:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 7:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 8:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 9:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 10:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 11:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 12:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 13:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 14:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 15:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 16:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 17:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 18:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 19:1. In certain embodiments, the antioxidant ispresent in the composition in a weight ratio of compound of Formula (I)to antioxidant of about 20:1.

In certain embodiments, provided herein is a composition or formulationas set forth in Table 1 (or oral dosage form comprising (e.g., dosageform comprising a capsule containing) such a composition or formulation)(e.g., wherein the total wt. % does not exceed 100%).

TABLE 1 Exemplary Compositions Formulation 1 Formulation 2 Formulation 3Component (% w/w) (% w/w) (% w/w) Solubilizer 15-50 20-40 25-30 Solventor Cosolvent(s) 15-50 25-50 35-40 (e.g., PEG) Surfactant  5-40  5-30 8-15 Emulsifier  5-40  5-30 10-20 Antioxidant 0.05-5   0.1-3   0.2-1  API >5 >7 >8.5

In some embodiments, any composition or formulation provided hereincomprises a solubilizer, solvent, surfactant, emulsifier, and/orantioxidant in an amount described in Table 1, irrespective of theamount of any other component (which may or may not be present, such asif achieving the beneficial results provided herein) of the composition.

In specific embodiments, provided herein is a composition or formulationcomprising the following components in the amounts (e.g., wt. % and/orabsolute mass) described in Table 2:

TABLE 2 Exemplary Composition Amount (e.g., in a 80 mg of compound ofAmount Component % w/w Formula (I) dosage form) (mg/g) Solubilizer 27.09236 mg  270.9 mg  PEG 38.83 338 mg  388.3 mg  Surfactant 10.84 94 mg 108.4 mg  Glyceride Emulsifier 13.54 118 mg  135.4 mg  Antioxidant 0.504 mg   5 mg  API 9.20 80 mg   92 mg 

Provided herein, in another aspect, is a pharmaceutical compositioncomprising:

-   -   a. a therapeutically effective amount of a compound of Formula        (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a % w/w of about 5 to about 40% (e.g.,        about 5 to about 30%, about 10 to about 20%);    -   c. a solubilizer, the solubilizer being present in the        composition in a % w/w of about 15 to about 50% (e.g., about 20        to about 40%, about 25 to about 30%);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a % w/w of about 15 to about 50%        (e.g., about 25 to about 50%, about 35 to about 40%);    -   e. a surfactant, the surfactant being present in the composition        in a % w/w of about 5 to about 40% (e.g., about 5 to about 30%,        about 8 to about 15%);    -   f. an antioxidant, the antioxidant being present in the        composition in a % w/w of about 0.05 to about 5% (e.g., about        0.1 to about 3%, about 0.2 to about 1%).

In certain embodiments, the composition is or is a part of aself-emulsifying drug dispersion (SEDD). In certain embodiments, thecomposition is a capsule fill formulation. In certain embodiments, thecomposition further comprises a capsule shell.

In certain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 50 mg/g (e.g., at least 60mg/g, at least 70 mg/g, at least 80 mg/g, or at least 90 mg/g) (e.g.,excluding the mass of a capsule shell). In certain embodiments, thecompound of Formula (I) is present in the formulation in a concentrationof at least 50 mg/g. In certain embodiments, the compound of Formula (I)is present in the formulation in a concentration of at least 60 mg/g. Incertain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 70 mg/g. In certainembodiments, the compound of Formula (I) is present in the formulationin a concentration of at least 80 mg/g. In certain embodiments, thecompound of Formula (I) is present in the formulation in a concentrationof at least 90 mg/g.

In certain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 60 mg/mL (e.g., at least 70mg/mL, at least 80 mg/mL, at least 90 mg/mL, or at least 100 mg/mL)(e.g., excluding the volume of a capsule shell). In certain embodiments,the compound of Formula (I) is present in the formulation in aconcentration of at least 60 mg/mL. In certain embodiments, the compoundof Formula (I) is present in the formulation in a concentration of atleast 70 mg/mL. In certain embodiments, the compound of Formula (I) ispresent in the formulation in a concentration of at least 80 mg/mL. Incertain embodiments, the compound of Formula (I) is present in theformulation in a concentration of at least 90 mg/mL. In certainembodiments, the compound of Formula (I) is present in the formulationin a concentration of at least 100 mg/mL.

In certain embodiments, at least 60 wt. % (e.g., at least 80 wt. %, atleast 90 wt. %, or at least 95 wt. %) of the compound of Formula (I) issoluble (dissolved) in the composition. In certain embodiments, at least60 wt. % of the compound of Formula (I) is soluble (dissolved) in thecomposition. In certain embodiments, at least 80 wt. % of the compoundof Formula (I) is soluble (dissolved) in the composition. In certainembodiments, at least 90 wt. % of the compound of Formula (I) is soluble(dissolved) in the composition. In certain embodiments, at least 95 wt.% of the compound of Formula (I) is soluble (dissolved) in thecomposition.

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising:

-   -   a. at least 40 mg (e.g., at least 50 mg, at least 60 mg, at        least 75 mg) of a compound of Formula (I):

-   -   b. an emulsifier (e.g., glyceride), the emulsifier being present        in the composition in a % w/w of about 5 to about 40% (e.g.,        about 5 to about 30%, about 10 to about 20%);    -   c. a solubilizer, the solubilizer being present in the        composition in a % w/w of about 15 to about 50% (e.g., about 20        to about 40%, about 25 to about 30%);    -   d. a polyethylene glycol (PEG), the polyethylene glycol being        present in the composition in a % w/w of about 15 to about 50%        (e.g., about 25 to about 50%, about 35 to about 40%);    -   e. a surfactant, the surfactant being present in the composition        in a % w/w of about 5 to about 40% (e.g., about 5 to about 30%,        about 8 to about 15%);    -   f. an antioxidant, the antioxidant being present in the        composition in a % w/w of about 0.05 to about 5% (e.g., about        0.1 to about 3%, about 0.2 to about 1%).

Provided herein, in another aspect, is an oral dosage form comprising apharmaceutical composition, the pharmaceutical composition comprising atleast 40 mg (e.g., at least 50 mg, at least 60 mg, or at least 75 mg) ofa compound of Formula (I):

In certain embodiments, the pharmaceutical composition comprises atleast 40 mg of a compound of Formula (I). In certain embodiments, thepharmaceutical composition comprises at least 50 mg of a compound ofFormula (I). In certain embodiments, the pharmaceutical compositioncomprises at least 60 mg of a compound of Formula (I). In certainembodiments, the pharmaceutical composition comprises at least 75 mg ofa compound of Formula (I).

In certain embodiments, the pharmaceutical composition further comprisesan emulsifier (e.g., glyceride). In certain embodiments, the emulsifieris present in the composition in a % w/w of about 5 to about 40% (e.g.,about 5 to about 30%, about 10 to about 20%, about 10% to about 15%). Incertain embodiments, the emulsifier is present in the composition in a %w/w of about 5%. In certain embodiments, the emulsifier is present inthe composition in a % w/w of about 10%. In certain embodiments, theemulsifier is present in the composition in a % w/w of about 15%. Incertain embodiments, the emulsifier is present in the composition in a %w/w of about 20%. In certain embodiments, the emulsifier is present inthe composition in a % w/w of about 25%. In certain embodiments, theemulsifier is present in the composition in a % w/w of about 30%. Incertain embodiments, the emulsifier is present in the composition in a %w/w of about 35%. In certain embodiments, the emulsifier is present inthe composition in a % w/w of about 40%.

In certain embodiments, the pharmaceutical composition further comprisesa solubilizer. In certain embodiments, the solubilizer is present in thecomposition in a % w/w of about 15 to about 50% (e.g., about 20 to about40%, about 25 to about 30%). In certain embodiments, the solubilizer ispresent in the composition in a % w/w of about 15%. In certainembodiments, the solubilizer is present in the composition in a % w/w ofabout 20%. In certain embodiments, the solubilizer is present in thecomposition in a % w/w of about 25%. In certain embodiments, thesolubilizer is present in the composition in a % w/w of about 30%. Incertain embodiments, the solubilizer is present in the composition in a% w/w of about 35%. In certain embodiments, the solubilizer is presentin the composition in a % w/w of about 40%. In certain embodiments, thesolubilizer is present in the composition in a % w/w of about 45%. Incertain embodiments, the solubilizer is present in the composition in a% w/w of about 50%.

In certain embodiments, the pharmaceutical composition further comprisesa polyethylene glycol (PEG). In certain embodiments, the polyethyleneglycol is present in the composition in a % w/w of about 15 to about 50%(e.g., about 25 to about 50%, about 35 to about 40%). In certainembodiments, the polyethylene glycol is present in the composition in a% w/w of about 15%. In certain embodiments, the polyethylene glycol ispresent in the composition in a % w/w of about 20%. In certainembodiments, the polyethylene glycol is present in the composition in aw/w of about 25%. In certain embodiments, the polyethylene glycol ispresent in the composition in a % w/w of about 30%. In certainembodiments, the polyethylene glycol is present in the composition in a% w/w of about 35%. In certain embodiments, the polyethylene glycol ispresent in the composition in a % w/w of about 40%. In certainembodiments, the polyethylene glycol is present in the composition in a% w/w of about 45%. In certain embodiments, the polyethylene glycol ispresent in the composition in a % w/w of about 50%.

In certain embodiments, the pharmaceutical composition further comprisesa surfactant. In certain embodiments, the surfactant is present in thecomposition in a % w/w of about 5 to about 40% (e.g., about 5 to about30%, about 8 to about 15%). In certain embodiments, the surfactant ispresent in the composition in a % w/w of about 5%. In certainembodiments, the surfactant is present in the composition in a % w/w ofabout 8%. In certain embodiments, the surfactant is present in thecomposition in a % w/w of about 9%. In certain embodiments, thesurfactant is present in the composition in a % w/w of about 10%. Incertain embodiments, the surfactant is present in the composition in a %w/w of about 11%. In certain embodiments, the surfactant is present inthe composition in a % w/w of about 12%. In certain embodiments, thesurfactant is present in the composition in a % w/w of about 15%.

In certain embodiments, the pharmaceutical composition further comprisesan antioxidant. In certain embodiments, the antioxidant is present inthe composition in a % w/w of about 0.05 to about 5% (e.g., about 0.1 toabout 3%, about 0.2 to about 1%). In certain embodiments, theantioxidant is present in the composition in a % w/w of about 0.05%. Incertain embodiments, the antioxidant is present in the composition in a% w/w of about 0.1%. In certain embodiments, the antioxidant is presentin the composition in a % w/w of about 0.2%. In certain embodiments, theantioxidant is present in the composition in a % w/w of about 0.3%. Incertain embodiments, the antioxidant is present in the composition in a% w/w of about 0.4%. In certain embodiments, the antioxidant is presentin the composition in a % w/w of about 0.5%. In certain embodiments, theantioxidant is present in the composition in a % w/w of about 0.6%. Incertain embodiments, the antioxidant is present in the composition in a% w/w of about 0.7%. In certain embodiments, the antioxidant is presentin the composition in a % w/w of about 0.8%. In certain embodiments, theantioxidant is present in the composition in a % w/w of about 0.9%. Incertain embodiments, the antioxidant is present in the composition in a% w/w of about 1%. In certain embodiments, the antioxidant is present inthe composition in a % w/w of about 2%. In certain embodiments, theantioxidant is present in the composition in a % w/w of about 3%. Incertain embodiments, the antioxidant is present in the composition in a% w/w of about 4%. In certain embodiments, the antioxidant is present inthe composition in a % w/w of about 5%.

In certain embodiments, the composition is as described in any of thepreviously described embodiments.

Provided in certain embodiments herein is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual any composition,formulation, or oral dosage described herein.

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a high dose of acompound of Formula (I):

the high dose of the compound of Formula (I) comprising administrationof at least 15 mg/kg/day of the compound of Formula (I) to theindividual.

In certain embodiments, the method comprises administering the compoundof Formula (I) in a total of no more than 25 oral dosage forms per day.In certain embodiments, the method comprises administering the compoundof Formula (I) in a total of no more than 0.3 oral dosage forms per 1 kgof mass of the individual per day. In certain embodiments, the methodcomprises administering the compound of Formula (I) in a total of nomore than 0.35 oral dosage forms per 1 kg of mass of the individual perday.

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a plurality of oraldosage forms, the plurality of oral dosage forms collectively comprisingtherapeutically effective amount of a compound of Formula (I):

Provided herein, in another aspect, is a method of treating fibrosis,cancer, or chronic inflammation in an individual in need thereof, themethod comprising administering to the individual a plurality of oraldosage forms, the plurality of oral dosage forms collectively comprisingtherapeutically effective amount of a compound of Formula (I):

the plurality of oral dosage forms comprising no more than 0.35 oraldosage forms for every 1 kg of mass of the individual per day (e.g., onaverage or maximum).

In certain embodiments, a cancer treated according to a method providedherein is a liver cancer, lung cancer, head and neck cancer, breastcancer, skin cancer, kidney cancer, testicular cancer, colon cancer,rectal cancer, gastric cancer, metastatic melanoma, prostate cancer,ovarian cancer, cervical cancer, bone cancer, spleen cancer, gallbladder cancer, brain cancer, pancreatic cancer, stomach cancer, analcancer, prostate cancer, multiple myeloma, post-transplantlymphoproliferative disease, restenosis, myelodysplastic syndrome,leukemia, lymphoma, or acute myelogenous leukemia. In some embodiments,a cancer treated according to a method provided herein is a livercancer, lung cancer, hepatocellular carcinoma, head and neck squamouscell carcinoma, non-small cell lung cancer, or estrogenreceptor-positive breast cancer. In some embodiments, a cancer treatedaccording to a method provided herein is head and neck cancer, lungcancer, liver cancer, breast cancer, ovarian cancer, colon cancer,multiple myeloma, leukemia, or pancreatic cancer. In some embodiments,the leukemia is acute myelogenous leukemia.

In some embodiments, chronic inflammation treated herein is inflammatorybowel disease (IBD), ulcerative colitis, Crohn's disease, asthma,anaphylaxis, cancer cachexia, chronic kidney disease cachexia,nonalcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis,multiple sclerosis, or pancreatitis. In some embodiments, chronicinflammation treated herein is inflammatory bowel disease (IBD),ulcerative colitis, Crohn's disease, asthma, anaphylaxis, cancercachexia, chronic kidney disease cachexia, or nonalcoholicsteatohepatitis (NASH). In some embodiments, the anaphylaxis comprisesanaphylactic shock.

In certain embodiments, the fibrosis is skin fibrosis (or dermalfibrosis), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrowfibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liverfibrosis, retroperitoneum, renal fibrosis, myelofibrosis, non-alcoholicfatty liver disease, steatohepatitis, systemic sclerosis (includingdiffuse systemic sclerosis or limited systemic sclerosis),endomyocardial fibrosis, myocardial infarction, atrial fibrosis,mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemicfibrosis, Keloid, arthrofibrosis, adhesive capsulitis, or cysticfibrosis. In certain embodiments, the fibrosis is skin fibrosis(scleroderma), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bonemarrow fibrosis, intestine fibrosis, pancreatic fibrosis, jointfibrosis, liver fibrosis, retroperitoneum, myelofibrosis, non-alcoholicfatty liver disease, steatohepatitis, or systemic sclerosis. In certainembodiments, the fibrosis is skin fibrosis (scleroderma), cardiacfibrosis, cirrhosis, or pulmonary fibrosis.

In certain embodiments, the fibrosis is fibrosis following exposure tocertain drugs such as chemotherapy, fibrosis following exposure toenvironmental or other toxins or allergens, fibrosis occurring after anischemia/reperfusion injury such as myocardial infarction orhypotension, fibrosis occurring after radiation, fibrosis followinghepatitis induced by alcohol, toxins, drugs or infections, primarybiliary cirrhosis, fibrosis following viral infections involving theheart, liver, or lung, and/or idiopathic retroperitoneal fibrosis.

In certain embodiments, any method provided herein is a method oftreating muscle wasting, muscle weakness, or cachexia. The muscleweakness and/or muscle wasting and/or cachexia may have an unknown causeor it may be associated with an underlying condition. The underlyingcondition may be a catabolic condition. In some embodiments, theunderlying medical condition associated with cachexia is least renalfailure, cancer, AIDS, HIV infection, chronic obstructive lung disease(including emphysema), multiple sclerosis, congestive heart failure,tuberculosis, familial amyloid polyneuropathy, acrodynia, hormonaldeficiency, metabolic acidosis, infectious disease, chronicpancreatitis, autoimmune disorder, celiac disease, Crohn's disease,electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever,long bone fracture, hyperthyroidism, prolonged steroid therapy, surgery,bone marrow transplant, atypical pneumonia, brucellosis, endocarditis,Hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome,polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus,myositis, polymyositis, dematomyosytis, rheumatological diseases,autoimmune disease, collagen-vascular disease, visceral leishmaniasis,prolonged bed rest, and/or addiction to drugs, such as amphetamine,opiates, or barbitutates.

In certain embodiments, any method provided herein is a method oftreating, preventing, or reducing the risk or severity of an allergicreaction. In some embodiments, the allergic reaction is inducedfollowing an exposure to an allergen. In some embodiments, the allergenis a food allergen (such as milk, legumes, shellfish, tree nuts, eggs,fish, soy, and wheat), an environmental allergen or seasonal allergen(such as pollen or mold), a venom allergen (such as from wasp, bee, ant,hornet, yellow jacket, or asp), a medication allergen (such asanesthetics, β-lactam antibiotics, aspirin, non-steroidalanti-inflammatory drug, chemotherapy, vaccine, protamine, or herbalpreparations), or latex. In some embodiments, the allergic reaction isanaphylaxis, anaphylactic shock, allergic rhinitis, urticaria, foodallergy, drug allergy, hymenoptera allerga, bronchial constriction,asthma, or eczema.

In certain embodiments, any method provided herein is a method oftreating a viral infection. In some embodiments, the viral infection isa chronic viral infection. In some embodiments, the chronic viralinfection is AIDS, HIV infection, Hepatitis B infection, Hepatitis Cvirus infection, or Epstein-Barr virus infection.

In certain embodiments, any method provided herein is a method oftreating graft-versus-host diseases, pulmonary lymphangioleiomyomatosis,chagasic cardiomyopathy, age-related macular degeneration, amyloidosis,astrogliosis in Alzheimer's or other neurodegenerative diseases, orfamilial amyloid polyneuropathy.

In certain embodiments, any method provided herein is a method oftreating a neurodegenerative disease. In some embodiments, theneurodegenerative disease is chemotherapy-induced peripheral neuropathy,diabetic neuropathy, or chemobrain.

In certain embodiments, any method provided herein is a method oftreating or reducing the risk or severity of insulin resistance. In someembodiments, the insulin resistance is a result of an underlyingcondition. In some embodiments, the insulin resistance is associatedwith muscle of the individual being treated. In some embodiments, theinsulin resistance is caused by any reason for the individual, such aselevated free fatty acids in the blood, obesity, being overweight,having visceral fat, having a high fructose intake, having inflammation,being inactive, dysbiosis of the gut microbiota, and/or beinggenetically predisposed. In certain embodiments, any method providedherein is a method of treating or reducing the risk or severity ofmedical conditions associated with insulin resistance or that arecomplications of insulin resistance at least in part, such as severehigh blood sugar; severe low blood sugar; heart attack; stroke; kidneydisease (including chronic, for example, chronic kidney disease (CKD));eye problems; cancer; non-alcoholic fatty liver disease (NAFLD);polycystic ovarian syndrome (PCOS); metabolic syndrome; diabetes; orAlzheimer's disease, for example. In certain embodiments, the insulinresistance is a hallmark of metabolic syndrome and type 2 diabetes.Metabolic syndrome is a group of risk factors associated with type 2diabetes and heart disease. Its symptoms include high bloodtriglycerides, blood pressure, belly fat, and blood sugar, as well aslow HDL (good) cholesterol levels.

In some embodiments, higher or lower pill burden is tolerated. Forexample, in some embodiments, no more than 1 oral dosage forms for every1 kg of mass of the individual is administered per day (e.g., on averageor maximum). In specific embodiments, no more than 0.8 oral dosage formsfor every 1 kg of mass of the individual is administered per day (e.g.,on average or maximum). In more specific embodiments, no more than 0.6oral dosage forms for every 1 kg of mass of the individual isadministered per day (e.g., on average or maximum). In still morespecific embodiments, no more than 0.5 oral dosage forms for every 1 kgof mass of the individual is administered per day (e.g., on average ormaximum). In yet more specific embodiments, no more than 0.4 oral dosageforms for every 1 kg of mass of the individual is administered per day(e.g., on average or maximum). In specific embodiments, no more than 0.3oral dosage forms for every 1 kg of mass of the individual isadministered per day (e.g., on average or maximum). In certainembodiments, lower (e.g., daily) doses of compounds of Formula (I)and/or lower pill burden are required in non-cancer therapies, such asin therapies for fibrosis and/or chronic inflammation. In someembodiments, no more than 0.2 oral dosage forms for every 1 kg of massof the individual is administered per day (e.g., on average or maximum).In specific embodiments, no more than 0.1 oral dosage forms for every 1kg of mass of the individual is administered per day (e.g., on averageor maximum).

In some embodiments, the pill burden discussed herein is associated withany suitable therapeutic (e.g., daily) dose of compound of Formula (I)and/or loading of compound of Formula (I) in the oral dosage form(s),such as any dose or amount described herein.

For example, in some embodiments, an oral dosage form provided hereincomprises any suitable amount of a compound of Formula (I), such asformulated according to any pharmaceutical composition described herein.In some embodiments, an oral dosage form provided herein comprises atleast 30 mg of a compound of Formula (I). In specific embodiments, anoral dosage form provided herein comprises at least 40 mg of a compoundof Formula (I). In more specific embodiments, an oral dosage formprovided herein comprises at least 50 mg of a compound of Formula (I).In still more specific embodiments, an oral dosage form provided hereincomprises at least 60 mg of a compound of Formula (I). In yet morespecific embodiments, an oral dosage form provided herein comprises atleast 70 mg of a compound of Formula (I). In specific embodiments, anoral dosage form provided herein comprises at least 80 mg of a compoundof Formula (I).

In certain embodiments, the method comprises administering at least 10mg/kg/day of the compound of Formula (I) to the individual. In certainembodiments, the method comprises administering at least 15 mg/kg/day ofthe compound of Formula (I) to the individual. In certain embodiments,the method comprises administering at least 20 mg/kg/day of the compoundof Formula (I) to the individual. In certain embodiments, the methodcomprises administering at least 25 mg/kg/day of the compound of Formula(I) to the individual.

Provided herein, in another aspect, is a method of providing to anindividual an improved C_(max) or AUC_(0-∞) of a compound of Formula(I):

the improved C_(max) or AUC_(0-∞) being at least 1.1 greater than theeffect obtained by administering an otherwise identical amount of acompound of Formula (I) in a formulation of PEG400 and Labrasol®.

In certain embodiments, the method has an administration protocol of anyof the previously described embodiments. In certain embodiments, thecompound of Formula (I) is administered in a pharmaceutical compositionor in one or more oral dosage forms of any of the previously describedembodiments.

In certain embodiments, the compound of Formula (I) is administered inany suitable amount. In certain embodiments, the compound of Formula (I)is administered in any suitable dosing interval. In certain embodiments,the compound of Formula (I) is administered once daily. In certainembodiments, the compound of Formula (I) is administered twice daily.

The following references illustrate the efficacy of the compound ofFormula (I) in certain therapies described herein and are incorporatedby reference in their entirety: Jung et al., Clin. Cancer Res. 2017,23(18), 5537-5546; Bharadwaj et al., Oncotarget 2016, 7(18),26307-26330; Lewis et al., Lung Cancer 2015, 90(2), 182-190; Kettner etal., Clin. Cancer Res. 2019, 25(13), 3996-4013; Gavino et al., Allergy2016, 71(12), 1684-1692; Hox et al., J. Allergy Clin. Immunol. 2016,138(1), 187-199; Silva et al., J Biol. Chem. 2015, 290(17), 11177-11187;Zhang et al., Cell Metab. 2013, 18(3), 368-379; Pedroza et al.,Rheumatology 2018, 57(10), 1838-1850; and Pedroza et al., The FASEBJournal 2016, 30(1), 129-140.

Provided herein, in another aspect, is a crystalline form of a compoundof Formula (I):

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern comprising peaks at 8.1±0.2°,16.5±0.2°, 18.4±0.2°, 21.8±0.2°, and 22.6±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 9.6±0.2°, 11.4±0.2°,12.7±0.2°, and 14.7±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises at least two peaks selectedfrom 9.6±0.2°, 11.4±0.2°, 12.7±0.2°, and 14.7±0.2° two theta. In certainembodiments, the X-ray powder diffraction pattern further comprises atleast three peaks selected from 9.6±0.2°, 11.4±0.2°, 12.7±0.2°, and14.7±0.2° two theta. In certain embodiments, the X-ray powderdiffraction pattern further comprises peaks at 9.6±0.2°, 11.4±0.2°,12.7±0.2°, and 14.7±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 19.7±0.2°, 20.2±0.2°,20.8±0.2°, and 24.4±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises at least two peaks selectedfrom 19.7±0.2°, 20.2±0.2°, 20.8±0.2°, and 24.4±0.2° two theta. Incertain embodiments, the X-ray powder diffraction pattern furthercomprises at least three peaks selected from 19.7±0.2°, 20.2±0.2°,20.8±0.2°, and 24.4±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises peaks at 19.7±0.2°,20.2±0.2°, 20.8±0.2°, and 24.4±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 26.1±0.2°, 29.3±0.2°, and30.7±0.2° two theta. In certain embodiments, the X-ray powderdiffraction pattern further comprises at least two peaks selected from26.1±0.2°, 29.3±0.2°, and 30.7±0.2° two theta. In certain embodiments,the X-ray powder diffraction pattern further comprises peaks at26.1±0.2°, 29.3±0.2°, and 30.7±0.2° two theta.

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern comprising peaks at 8.1±0.2°, 9.6±0.2°,11.4±0.2°, 12.7±0.2°, 14.7±0.2°, 16.5±0.2°, 18.4±0.2°, from 19.7±0.2°,20.2±0.2°, 20.8±0.2°, 21.8±0.2°, 22.6±0.2°, 24.4±0.2°, 26.1±0.2°,29.3±0.2°, and 30.7±0.2° two theta.

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern comprising peaks at 8.13±0.2°,16.50±0.2°, 18.41±0.2°, 21.77±0.2°, and 22.64±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 9.56±0.2°, 11.43±0.2°,12.75±0.2°, and 14.66±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises at least two peaks selectedfrom 9.56±0.2°, 11.43±0.2°, 12.75±0.2°, and 14.66±0.2° two theta. Incertain embodiments, the X-ray powder diffraction pattern furthercomprises at least three peaks selected from 9.56±0.2°, 11.43±0.2°,12.75±0.2°, and 14.66±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises peaks at 9.56±0.2°,11.43±0.2°, 12.75±0.2°, and 14.66±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 19.70±0.2°, 20.21±0.2°,20.81±0.2°, and 24.43±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises at least two peaks selectedfrom 19.70±0.2°, 20.21±0.2°, 20.81±0.2°, and 24.43±0.2° two theta. Incertain embodiments, the X-ray powder diffraction pattern furthercomprises at least three peaks selected from 19.70±0.2°, 20.21±0.2°,20.81±0.2°, and 24.43±0.2° two theta. In certain embodiments, the X-raypowder diffraction pattern further comprises peaks at 19.70±0.2°,20.21±0.2°, 20.81±0.2°, and 24.43±0.2° two theta.

In certain embodiments, the X-ray powder diffraction pattern furthercomprises at least one peak selected from 26.10±0.2°, 29.29±0.2°, and30.75±0.2° two theta. In certain embodiments, the X-ray powderdiffraction pattern further comprises at least two peaks selected from26.10±0.2°, 29.29±0.2°, and 30.75±0.2° two theta. In certainembodiments, the X-ray powder diffraction pattern further comprisespeaks at 26.10±0.2°, 29.29±0.2°, and 30.75±0.2° two theta.

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern comprising peaks at 8.13±0.2°,9.56±0.2°, 11.43±0.2°, 12.75±0.2°, 14.66±0.2°, 16.50±0.2°, 18.41±0.2°,from 19.70±0.2°, 20.21±0.2°, 20.81±0.2°, 21.77±0.2°, 22.64±0.2°,24.43±0.2°, 26.10±0.2°, 29.29±0.2°, and 30.75±0.2° two theta.

In certain embodiments, the crystalline form is characterized by anX-ray powder diffraction pattern substantially as set forth in FIG. 1.

EXAMPLES Example 1: Two-Component Formulation System

A formulation of the compound dissolved in Labrasol®/PEG400 (60:40) andencapsulated into a hard gelatin capsule (unit dose: 36 mg), whileshowing encouraging results in 3 dose cohorts, was prevented fromadvancing to a fourth patient cohort (25.6 mg/kg/day as 12.8 mg/kg twicedaily (BID) doses) because of an unacceptably high pill burden. Forexample, a 70 kg subject in Cohort 4 would require 60 capsules per daysplit into BID doses.

In order to reduce the pill burden and allow the further therapeuticdevelopment of the compound of Formula (I), a second-generationformulation was developed. This formulation contains 80 mg of thecompound of Formula (I) per capsule. The 80 mg strength will reducecapsule burden approximately 2.7-fold; the 70 kg subject in Cohort 4would take 22 capsules per day split into BID doses. The formulationcomprises the compound of Formula (I), Kolliphor® RH 40 (PEG-40hydrogenated castor oil), PEG600, Polysorbate 20, Labrasol®, and citricacid.

Example 2: Multiple-Component Formulations

Solubility of a compound of Formula (I) was evaluated in variousexcipient combinations set forth in Table 3 below. To determinesolubility, an excess amount of the compound of Formula (I) was added topre-mixed excipient combinations (according to the relative ratio of theexcipients as shown in Table 3) and agitated on a shaker protected fromlight for 2 days at room temperature for liquid excipient combinations.For semi-solid mixtures, the agitation was conducted at 50° C. for 2days. After 2 days, the samples were centrifuged at 14,000 rpm for 10minutes, and the supernatants were collected to assess the solubility ofa compound of Formula (I) (concentration) in the various excipientcombinations by high performance liquid chromatograph (HPLC). Theresulting concentrations of the compound of Formula (I) are summarizedin Table 3:

TABLE 3 Solubility of the Compound of Formula (I) in VariousFormulations Excipient Ratio Compound of Formula (I) mixture #Excipients w % Concentration (mg/g) 1 Labrasol ® 30 69.2 Kolliphor ® 45RH40 PEG 600 15 Polysorbate 80 10 2 Labrasol ® 20 94.3 Kolliphor ® 45RH40 PEG 600 15 Polysorbate 80 10 Transcutol ® HP 10 3 Labrasol ® 3077.5 Gelucire ® 48/16 45 PEG 600 15 Polysorbate 80 10 4 Labrasol ® 3057.1 Gelucire ® 44/14 45 PEG 600 15 Polysorbate 80 10 5 Kolliphorg 4563.2 RH40 PEG 600 15 Polysorbate 80 10 Propylene glycol 30 6 Labrasol ®30 95.2 Kolliphor ® 45 RH40 PEG 600 15 Polysorbate 20 10 7 Kolliphor ®45 86.2 RH40 PEG 600 35 Polysorbate 20 10 Transcutol ® HP 10 8Kolliphorg 45 82.5 RH40 PEG 600 30 Polysorbate 20 10 Labrasol ® 15 9Kolliphor ® 30 93.0 RH40 PEG 600 40 Polysorbate 20 10 Labrasol ® 20 10Labrasol ® 15 103.2 Kolliphor ® 30 RH40 PEG 600 43 Polysorbate 20 12 11Kolliphor ® 40 102.9 RH40 PEG 600 48 Polysorbate 20 10 Transcutol ® HP 212 Kolliphor ® 40 79.7 RH40 PEG 600 48 Polysorbate 20 10 Transcutol ® HP2 13 Propylene glycol 20 83.5 Kolliphor ® 40 RH40 PEG 600 25 Polysorbate20 10 Transcutol ® HP 5 14 Kolliphor ® 40 90.5 RH40 PEG 600 45Polysorbate 20 10 Transcutol ® HP 5 15 Vitamin E TPGS 40 44.2 PEG 600 50Polysorbate 20 10 16 Kolliphor ® 40 81.2 RH40 PEG 600 30 Polysorbate 2010 Capryol ®90 20 17 Kolliphor ® 40 97.5 RH40 PEG 600 40 Polysorbate 2010 Capryol ® 90 10 18 Vitamin E TPGS 40 68.5 PEG 600 40 Polysorbate 2010 Capmul ® MCM 10 EP 19 Vitamin E TPGS 40 71.1 PEG 600 40 Polysorbate20 10 Capmul ® C8 EP 10 20 Vitamin E TPGS 40 73.3 PEG 600 40 Polysorbate20 10 Capmul ® MCM 10

Example 3: Dispersion Testing

The three exemplary formulations were prepared at concentrationsapproximately 10% lower than the equilibrium concentrations observed inthe solubility assay of Example 2 to ensure that the compound of Formula(I) does not precipitate out during storage.

To prepare the bulk formulations, the excipients (according to therelative ratio of the excipients as shown in Table 4) were weighted inglass vials and agitated on a shaker at 50° C. to form homogeneoussolutions. The compound of Formula (I) was then weighed into theexcipient mixtures and placed at room temperature (Formulations A and B)or 50° C. (Formulation C). The resulting mixtures were protected fromlight and agitated until the compound of Formula (I) was completelydissolved. The composition of the formulations is summarized in Table 4:

TABLE 4 Exemplary Formulations Formula (I) Formulation Excipients Ratiow % Concentration (mg/g) A Labrasol ® 15 90 Kolliphor ® 30 RH40 PEG 60043 Polysorbate 20 12 B Kolliphor ® 40 90 RH40 PEG 600 40 Polysorbate 2010 Capryol ® 90 10 C Vitamin E 40 60 TPGS PEG 600 40 Polysorbate 20 10Capmul ® MCM 10

Formulations A and B required more than 24 hours for full dissolution,while Formulation C was fully dissolved within 8 hours. Formulations Aand B were dark red, viscous solutions, while Formulation C was asemi-solid solution.

Example 4: Dispersion and Characterization

The three exemplary formulations of Example 3 and the 60:40Labrasol®/PEG400 formulation (40 mg/mL) were tested for dispersity insimulated gastric/intestinal fluids. Simulated gastric fluid (FaSSGF)(pH 1.6) and fasted state simulated intenstinal fluid (FaSSIF) (pH 6.5)were prepared using FaSSIF/FeSSIF/FaSSGF powder according to themanufacturer's instructions.

The bulk formulations (0.3 g Formulation A, 0.3 g Formulation B, 0.4 gFormulation C, 0.6 g Labrasol®/PEG400 formulation) were dispersed in 5mL of FaSSGF (pH 1.6) to form the Stage 1 dispersions. The Stage 1dispersions were further diluted using FaSSIF (pH 6.5) at a 1:1 ratio(v/v) to form the Stage 2 dispersions, which were subsequently dilutedin one more volume of FaSSIF to form the Stage 3 dispersions.Dispersions from each stage were evaluated for droplet size by MalvernNano Series, visual inspection, and microscopy. The dispersions werefurther diluted in DI water for droplet size determination by dynamiclight scattering (DLS). The results of the droplet size and dispersionstudies are summarized in Table 5:

TABLE 5 Formulations Droplet Size by DLS Stage 1 Stage 2 Stage 3 SizeSize Size Formulation (nm) PdI (nm) PdI (nm) PdI A (90 mg/g) 123 0.22121 0.24 120 0.22 B (90 mg/g) 112 0.23 126 0.38 110 0.26 C (60 mg/g) 250.21 23 0.18 19 0.15 Labrasol ®/PEG400 3024 0.60 2976 0.39 680 0.87 (40mg/g) PdI = polydispersity index

The droplet size of Formulation A and Formulation B ranged from 110 nmto 130 nm with polydispersity indexes (PdI) of 0.2 or 0.3, whileFormulation C had a smaller droplet size of approximately 20 nm. Incontrast, the Labrasol®/PEG400 formulation displayed large andinhomogeneous droplet size and distribution.

Following dispersion, Formulation A, Formulation B, and theLabrasol®/PEG400 formulation were white opaque emulsions, whileFormulation C was a clear solution, e.g., due to its small droplet size.After sitting without agitation for 30 minutes, the Labrasol®/PEG400formulation coalesced on the bottoms of the vials, while the exemplaryformulations remained as emulsions. After 2 hours, Formulation Bflocculated.

Immediately following dispersion, the dispersions were analyzed bymicroscopy. Uniform droplets were observed for Formulation A andFormulation B for all three stages of dispersion. No droplets wereobserved in Formulation C, e.g., due to the small droplet size. TheLabrasol®/PEG400 formulation dispersions displayed diverse droplet size,matching the observation from the dynamic light scattering measurement.

Dissolution profiles in simulated GI fluids were also analyzed, withFormulations A and C both showing comparable (e.g., about 80-120%, about90-110%, or the like) or improved release in simulated GI fluid systemsrelative to Labrasol®/PEG400 formulation, as shown in FIG. 2 and FIG. 3.

Example 5: Stability Testing

Studies have shown that the compound of Formula (I) is susceptible tooxidation. Stability was analyzed using a variety of antioxidants. Abulk formulation containing Kolliphor® RH 40, PEG600, Polysorbate 80,Labrasol®, and Transcutol® HP (45:15:10:20:10 by weight) was preparedwith a compound of Formula (I) concentration of 60 mg/g. Antioxidants,including Vitamin E (0.05 wt %), ascorbyl palmitate (0.05 wt %),butylated hydroxytoluene (0.005 wt %), and triethyl citrate (0.7 wt %)were dissolved/dispersed in the bulk formulation, respectively. Theresulting samples were placed at room temperature in glass vials andprotected from light. The samples were monitored for purity by HPLC at0, 3, and 8 weeks. The results of the stability study are summarized inTable 6:

TABLE 6 Stability Test 0 Weeks 3 Weeks 8 Weeks API Purity Area APIPurity Area API Purity Area Antioxidants (%) (%) (%) Without 99.05 79.9387.15 antioxidant Vitamin E 98.95 80.14 89.48 Ascorbyl 98.80 83.65 90.59palmitate Butylated 98.96 81.08 88.76 hydroxytoluene Triethyl 98.5180.58 88.82 citrate

0.05 wt % ascorbyl palmitate showed the best antioxidant effect comparedto the other antioxidants tested.

To confirm the effectiveness of antioxidants, Formulation A andFormulation C at 90 mg/g and 60 mg/g, respectively, were prepared withor without 0.5 wt % citric acid. The resulting formulations were placedin a stability chamber at room temperature and 60% relative humidity,and purity was monitored over the course of 5 months. TheLabrasol®/PEG400 formulation with 0.5 wt % citric acid was tested as acontrol. The results of this stability study are summarized in Table 7:

TABLE 7 Effectiveness of Antioxidant 0 Months 2 Months 5 Months APIPurity Area API Purity Area API Purity Area Formulations (%) (%) (%)Labrasol ®/PE 95.3 96.1 99.6 G400 + 0.5% Citric Acid Formulation A +90.7 92.6 98.3 0.5% Citric Acid Formulation A 76.6 84.6 83.6 FormulationC + 92.8 96.9 N/A 0.5% Citric Acid Formulation C 89.3 91.4 N/A

After two months, purity of the compound of Formula (I) wassignificantly lower in samples without citric acid. For Formulation Awith citric acid, the purity of the compound of Formula (I) was 92.6%versus 84.6% for the same bulk solution without citric acid. Citric acidshowed a similar protective effect against oxidation in Formulation C aswell. At 5 months, Formulation A with citric acid was 98.3% pure versus83.6% without citric acid, confirming the viability of citric acid as anantioxidant to ensure the long-term stability of the compound of Formula(I).

Formulation D comprises a compound of Formula (I) dissolved at aconcentration of 92 mg/g in a mixture of Kolliphor® RH 40 (PEG-40hydrogenated castor oil), PEG600, Polysorbate 20, Labrasol®, and citricacid. An 80 mg dosage is accomplished by a 0.87 g fill in a size 00capsule. The composition of Formulation D is shown in Table 8:

TABLE 8 Formulation D Component % w/w Amount per 80 mg capsuleKolliphor ® RH 40 27.09 236 mg  PEG600 38.83 338 mg  Polysorbate 2010.84 94 mg  Labrasol ® 13.54 118 mg  Citric acid 0.50 4 mg Compound ofFormula (I) 9.20 80 mg 

Example 6: Stability Study

Stability of Formulation D was evaluated on the bulk formulationsolution at 5° C. and 25° C. for 5 months. The results of the stabilitystudy are summarized in Table 9:

TABLE 9 5-Month Stability Temperature API 5° C. 99.9% 25° C.  98.3%

Example 7: Rat Pharmacokinetics (PK) Study

The pharmacokinetics of Formulation D and Labrasol®/PEG400 formulationswere compared in a rat study. A single oral dose of 25 mg/kg of thecompound of Formula (I) was administered in four groups. The dosevolumes for Groups 1 to 4 were 10, 10, 10, and 3 mL/kg, respectively.Group 1 received the Labrasol®/PEG400 formulation neat (undiluted).Group 2 received the Labrasol®/PEG400 formulation diluted as a 1:9oil-in-water dispersion. Group 3 received Formulation D diluted as a 1:9oil-in-water dispersion. Group 4 received Formulation D diluted as a 1:2oil-in-water dispersion. The design of the rat pharmacokinetics study issummarized in FIG. 4.

Blood samples were collected over a 48-hour period at pre-dose, 0.25-,0.5-, 1-, 2-, 4-, 8-, 24-, and 48-hour intervals. Concentration of thecompound of Formula (I) was determined via a validated LC/MS/MS assay.Non-compartmental pharmacokinetic parameters were calculated withPhoenix WinNonlin (v8.1). The comparative pharmacokinetic parametersthus obtained are summarized in Table 10:

TABLE 10 Summary of Comparative PK Parameters in the Rat After a 25mg/kg Dose Group 1 Group 2 Labrasol ®/ Labrasol ®/ Group 3 Group 4Formulation PEG400 PEG400 D D Dilution neat 1:9 1:9 1:2 Volume 10 10 103 Dose (mg/kg) 24.4 20.4 25.7 26.3 T_(max) (h) 8 4 1 1 C_(max) (ng/mL)5,560 7,340 11,200 16,700 C_(max)_D 228 360 436 635 (kg * ng/mL/mg)AUC_(last) (h * ng/mL) 115,000 75,600 129,000 121,000 AUC_(∞)_D_obs 47503790 5070 4610 (h * kg * ng/mL/mg) Plasma half-life (h) 6.11 7.89 6.945.12

Both neat and oil-in-water dispersion preparations of theLabrasol®/PEG400 formulation displayed slower rates of oral absorptioncompared to Formulation D preparations, as evidenced by the greaterT_(max) values observed for Groups 1 and 2 (8 and 4 hours, respectively,versus 1 hour). Both Formulation D preparations also resulted in higherC_(max) values (11,200 and 16,700 ng/mL) compared to theLabrasol®/PEG400 groups (5,560 and 7,340 ng/mL). This 2-3 fold differentis likely due to faster absorption by Formulation D.

The overall systemic exposure (AUC_(last)) of Formulation D preparations(129,000 and 121,000 h*ng/mL) were comparable (e.g., about 80-120%,about 90-110%, or the like) to the neat Labrasol®/PEG400 formulation(115,000 h*ng/mL). The oil-in-water dispersion preparation of theLabrasol®/PEG400 formulation resulted in the lowest systemic exposure(75,600 h*ng/mL). When AUC was normalized by dose for 0 to infinity(AUC_(∞)_D_obs), Groups 1, 3, and 4 values were comparable (e.g., about80-120%, about 90-110%, or the like) at 4,754; 5,070; and 4,610h*kg*ng/mL/mg, respectively. Only the oil-in-water dispersionpreparation of the Labrasol®/PEG400 formulation resulted in a lesservalue (3,790 h*kg*ng/mL/mg).

The different dispersion ratios and dose volumes of the two FormulationD preparations (3 mL for 1:2 and 10 mL for 1:9) did not result indifferences in systemic exposure, as evidenced by similar AUC_(last)values. Thus, the higher C_(max) value of the 1:2 preparation versus the1:9 Formulation D preparation appears to be attributable to the rates ofabsorption, not to differences in systemic exposure. This observation isfurther confirmed by the comparable (e.g., about 80-120%, about 90-110%,or the like) AUC∞_D_obs values (5,070 vs. 4,610 h*kg*ng/mL/mg) for the1:9 and 1:2 preparations, respectively.

The neat Labrasol®/PEG400 formulation preparation showed comparable(e.g., about 80-120%, about 90-110%, or the like) total systemicexposure (AUC_(last)) and dose-normalized AUC (AUC∞_D_obs) to bothFormulation D preparations. The 1:9 Labrasol®/PEG400 formulationpreparation has markedly lower AUC_(last) and AUC∞_D_obs values buthigher C_(max) and C_(max)_D values compared to the neat preparation.The 1:9 preparation also displayed the longest plasma eliminationhalf-life (7.89 hours). When taken together, these parameters indicatethat the 1:9 preparation has an altered absorption profile compared tothe neat preparation. This difference in absorption profile impactedtotal exposure and may have been responsible for delayed elimination.

Both Formulation D preparations showed comparable (e.g., about 80-120%,about 90-110%, or the like) total system exposure (AUC) and plasmahalf-life to the neat Labrasol®/PEG400 formulation preparation. TheFormulation D resulted in an increased rate of absorption, with adecreased T_(max) and an increased C_(max) relative to theLabrasol®/PEG400 formulation.

Example 8: Human Pharmacokinetic (PK) Study (2-Component)

Pharmacokinetic data obtained for 13 human subjects treated with thetwo-component formulation system of Example 1 is summarized herein.Subjects 1, 4, 6, and 7 were enrolled in Cohort 1 (3.2 mg/kg/day);Subjects 8, 9, and 10 were enrolled in Cohort 2 (6.4 mg/kg/day); andSubjects 11, 12, 15, 16, 19, and 20 were enrolled in Cohort 3 (12.8mg/kg/day). The plasma samples from the first BID dose on Cycle 1/Day 1were analyzed for all 13 subjects. The dosage levels were achieved withBID dosing. Thus, for Cohort 1, 3.2 mg/kg/day was 1.6 mg/kg BID; forCohort 2, 6.4 mg/kg/day was 3.2 mg/kg BID; and for Cohort 3, 12.8mg/kg/day was 6.4 mg/kg BID.

The individual pharmacokinetic parameters by cohort for the 12-hour timecourse of a single dose by subject are summarized in FIG. 5.

Individuals in Cohort 1 (1.6 mg/kg BID) demonstrated a T_(max) thatranged from 0.82 to 4 hours and a C_(max) that ranged from 735 to 1,380ng/mL. The C_(max) normalized by dose (C_(max) D) ranged from 4.9 to 9.2ng/mL/mg. The AUC_(last) ranged from 5,430 to 7,640 h*ng/mL. Whennormalized by dose, the AUC_(last) D ranged from 30.1 to 43.8h*ng/mL/mg.

Individuals in Cohort 2 (3.2 mg/kg BID) demonstrated a T_(max) thatranged from 1.1 to 2 hours and a C_(max) that ranged from 1,910 to 3,260ng/mL. The C_(max) normalized by dose (C_(max) D) ranged from 6.2 to12.1 ng/mL/mg. The AUC_(last) ranged from 11,700 to 19,800 h*ng/mL. Whennormalized by dose, the AUC_(last) D ranged from 32.5 to 73.3h*ng/mL/mg.

Individuals in Cohort 3 (6.4 mg/kg BID) demonstrated a T_(max) thatranged from 1 to 6.1 hours and a C_(max) that ranged from 2,220 to 3,730ng/mL. The C_(max) normalized by dose (C_(max) D) ranged from 4.91 to7.77 ng/mL/mg. The AUC_(last) ranged from 12,700 to 29,200 h*ng/mL. Whennormalized by dose, the AUC_(last) D ranged from 28.2 to 60.8h*ng/mL/mg.

The mean pharmacokinetic parameters by cohort for the 12-hour timecourse of a single dose are summarized in FIG. 6.

Cohort 1 demonstrated mean values for T_(max), C_(max), C_(max) D,AUC_(last), and AUC_(last) D of 1.91 hours, 1,090 ng/mL, 6.33 ng/mL/mg,6,360 h*ng/mL, and 36.9 h*ng/mL/mg, respectively.

Cohort 2 demonstrated mean values for T_(max), C_(max), C_(max) D,AUC_(last), and AUC_(last) D of 1.39 hours, 2,460 ng/mL, 8.73 ng/mL/mg,14,800 h*ng/mL, and 53 h*ng/mL/mg, respectively.

Cohort 3 demonstrated mean values for T_(max), C_(max), C_(max) D,AUC_(last), and AUC_(last) D of 2.74 hours, 2,690 ng/mL, 5.81 ng/mL/mg,19,200 h*ng/mL, and 41.7 h*ng/mL/mg, respectively.

Example 9: Spray Dried Dispersion (SDD) and Nanosuspension Formulations

A spray dried dispersion (SDD) formulation of the compound of Formula(I) was prepared as follows. A spray dried dispersion of the compound ofFormula (I) in EUDRAGIT® E PO (375 mg, 20% drug loading) was suspendedin 0.5% hydroxypropyl methylcellulose (HPMC) 603/0.2% Tween 80 solution(30 mL) with 30 seconds of shaking followed by 15 minutes of stirringwith a magnetic stir bar. The resulting suspension was shaken gently for15 seconds prior to dosing.

A nanosuspension of the compound of Formula (I) was prepared as follows.A nanosuspension of the compound of Formula (I) in 1% Tween80 (1.0 mL,101.37 mg/mL) was vortexed for 15-20 seconds and then transfer to USPwater (39.5 mL). The resulting suspension was vortexed for 15-20 secondsprior to dosing.

When subjected to a rat pharmacokinetics study, the spray drieddispersion and the nanosuspension gave results as shown in FIG. 7. Asdemonstrated, not only were the nanosuspension and the SDD formulationsignificantly inferior to the multi-component formulations providedherein, but were also inferior to the 2-component (Labrasol®/PEG400)formulation as well in C_(max) and AUC.

Example 10: Human Bioavailability and Pharmacokinetic (PK) StudyComparing 2-Component Formulation and Self-Emulsifying-Drug-Dispersion(SEDD) Formulation

A total of 14 subjects diagnosed with advanced cancers were administeredthe compound of Formula (I) dosed at 12.8 mg/kg/day using thetwo-component (Labrasol®/PEG400) formulation system of Example 1 (8subjects) or at 12.8 mg/kg/day using the SEDD formulation described inExamples 1 and 5 (6 subjects). Plasma concentrations of a compound ofFormula (I) were used for the evaluation of oral bioavailability andpharmacokinetics.

Blood Collection: PK sampling was performed at the following time pointsfor Cycle 1/Day 1 (C1/D1): pre-dose, 1, 2, 4, 6, 8, 11:59 hr Post 1^(st)dose (before 2^(nd) dose) and at 23:59 hr Post 1^(st) dose (before3^(rd) dose). Variability in timepoints was allowed at ±15 minutes forthe 1, 2, and 4 hr time points and ±30 minutes for the 6, 8, 12 and 24hr time points.

Results

Human PK Data through the 12-hour time point:

The plasma samples from the first BID dose (6.4 mg/kg) on Cycle 1/Day 1were analyzed for all 14 subjects. The mean area under the curve (AUC),controlling dose and body weight was 2,982 ng*hr/mL in the cohort usingthe Labrasol®/PEG formulation and 5,198 ng*hr/mL in the cohort usingFormulation D. This resulted in a 74% increase in plasma drug exposureamong the cohort using Formulation D as shown in FIG. 8.

Safety:

In addition to improved AUC, the SEDD formulation (Formulation D) hasdemonstrated an improved safety profile. Four of the 8 subjects in thecohort using the Labrasol®/PEG formulation reported adverse events (AEs)deemed attributable to the drug in the Labrasol/PEG formulation,including 3 Grade 3 events.

No subjects in the cohort using Formulation D reported any eventsattributable to the drug dosed in the SEDD formulation as outlined inTable 11:

TABLE 11 Safety Analysis of Subjects Dosed at 12.8 mg/kg/day NumberNumber of of subjects Formulation/Type of Adverse Events reported AEreporting AE Labrasol/PEG Formulation Dose (n = 8) 19 4 Constitutional**Grade 1 3 Grade 2 3 Gastrointestinal Grade 1 5 Grade 2 5 Grade 3 3Formulation D Dose (n = 6) 0 0 *Safety analysis based on 14 subjectstreated at dose of 12.8 mg/kg/day. **Constitutional includes fatigue,appetite changes, and weight loss.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A pharmaceutical composition comprising: a. atleast 50 mg of a compound of Formula (I):

b. a glyceride emulsifier present in the composition in a weight ratioof compound of Formula (I) to emulsifier of about 1:1; c. a solubilizerpresent in the composition in a weight ratio of compound of Formula (I)to solubilizer of about 1:3, wherein the solubilizer is polyoxyl castoroil; d. a polyethylene glycol (PEG) present in the composition in aweight ratio of compound of Formula (I) to polyethylene glycol of about1:4; e. a surfactant present in the composition in a weight ratio ofcompound of Formula (I) to surfactant of about 1:2, wherein thesurfactant is polysorbate; and f. an antioxidant present in thecomposition in a weight ratio of compound of Formula (I) to antioxidantof about 20:1.
 2. The pharmaceutical composition of claim 1, wherein thepolyoxyl castor oil is PEG-40 hydrogenated castor oil.
 3. Thepharmaceutical composition of claim 1, wherein the PEG has an averagemolecular weight of about 200 to about 1000 Da.
 4. The pharmaceuticalcomposition of claim 1, wherein the polysorbate is polysorbate
 20. 5.The pharmaceutical composition of claim 1, wherein the antioxidant iscitric acid.
 6. The pharmaceutical composition of claim 1, wherein atleast 50 mg of the glyceride emulsifier, at least 150 mg of thesolubilizer, at least 200 mg PEG, at least 100 mg of surfactant, and atleast 2.5 mg of the antioxidant are present in the pharmaceuticalcomposition.
 7. An oral dosage form comprising the pharmaceuticalcomposition of claim 1 contained within a capsule.
 8. A method oftreating cancer in an individual in need thereof, the method comprisingadministering to the individual the oral dosage form of claim
 7. 9. Themethod of claim 8, wherein the cancer is head and neck cancer, lungcancer, liver cancer, breast cancer, ovarian cancer, colon cancer,multiple myeloma, prostate cancer, cervical cancer, brain cancer,pancreatic cancer, myelodysplastic syndrome, leukemia, lymphoma,neuroblastoma, kidney cancer, or metastatic melanoma.
 10. The method ofclaim 8, wherein the cancer is head and neck cancer, lung cancer, livercancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma,leukemia, or pancreatic cancer.
 11. A method of treating fibrosis in anindividual in need thereof, the method comprising administering to theindividual the oral dosage form of claim
 7. 12. The method of claim 11,wherein the fibrosis is associated with pulmonary fibrosis, intestinefibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis,retroperitoneal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholicfatty liver disease, steatohepatitis, or systemic sclerosis.
 13. Themethod of claim 11, wherein the fibrosis is associated with pulmonaryfibrosis, non-alcoholic fatty liver disease, steatohepatitis, orsystemic sclerosis.
 14. A method of treating chronic inflammation in anindividual in need thereof, the method comprising administering to theindividual the oral dosage form of claim
 7. 15. A method of treatingchemotherapy-induced peripheral neuropathy in an individual in needthereof, the method comprising administering to the individual the oraldosage form of claim
 7. 16. A method of treating diabetic neuropathy inan individual in need thereof, the method comprising administering tothe individual the oral dosage form of claim
 7. 17. A method of treatingfamilial amyloid polyneuropathy in an individual in need thereof, themethod comprising administering to the individual the oral dosage formof claim
 7. 18. A method of treating cachexia in an individual in needthereof, the method comprising administering to the individual the oraldosage form of claim
 7. 19. A method of treating anaphylaxis anindividual in need thereof, the method comprising administering to theindividual the oral dosage form of claim 7.